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{{short description|Rejection of transplanted tissue by the recipient's immune system}}
{{Refimprove|date=November 2007}}
{{Redirect|Host-versus-graft disease|the condition in which transplanted cells attack the recipient's cells|Graft-versus-host disease}}
{{Redirect|Host-versus-graft disease|the condition in which transplanted cells attack the recipient's cells|Graft-versus-host disease}}


{{Infobox disease
{{Infobox medical condition (new)
|Name = Transplant rejection
| name = Transplant rejection
|Image = Lung transplant rejection - high mag.jpg
| synonyms =
| image = Lung transplant rejection - high mag.jpg
|Caption = [[Micrograph]] showing [[lung transplant]] rejection. Lung [[biopsy]]. [[H&E stain]].
| caption = [[Micrograph]] showing [[lung transplant]] rejection. Lung [[biopsy]]. [[H&E stain]].
|DiseasesDB =
| pronounce =
|ICD10 = {{ICD10|T|86||t|80}}
| field =
|ICD9 =
| symptoms =
| complications =
|MedlinePlus = 000815
|eMedicineSubj =
| onset =
| duration =
|eMedicineTopic =
| types =
|eMedicine_mult =
|MeshID = D006084
| causes =
| risks =
}}
| diagnosis =
'''Transplant rejection''' occurs when [[Organ transplant|transplanted]] tissue is rejected by the recipient's [[immune system]], which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of [[immunosuppressant drugs]] after transplant.<ref name="pmid11158412">{{cite journal|last=Frohn|first=C|author2=Fricke, L |author3=Puchta, JC |author4= Kirchner, H |title=The effect of HLA-C matching on acute renal transplant rejection.|journal=Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association|date=Feb 2001|volume=16|issue=2|pages=355–60|doi=10.1093/ndt/16.2.355|pmid=11158412|url=http://ndt.oxfordjournals.org/content/16/2/355.full}}</ref>
| differential =
| prevention =
| treatment =[[Immunosuppressive drugs]]
| medication =
| prognosis =
| frequency =
| deaths =
|alt=|specialty=[[Immunology]]}}
'''Transplant rejection''' occurs when [[Organ transplant|transplanted]] tissue is rejected by the recipient's [[immune system]], which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of [[immunosuppressant drugs]] after transplant.<ref name="pmid11158412">{{cite journal | vauthors = Frohn C, Fricke L, Puchta JC, Kirchner H | title = The effect of HLA-C matching on acute renal transplant rejection | journal = Nephrology, Dialysis, Transplantation | volume = 16 | issue = 2 | pages = 355–360 | date = February 2001 | pmid = 11158412 | doi = 10.1093/ndt/16.2.355 | doi-access = free }}</ref>


==Types==
==Pretransplant rejection prevention==
Transplant rejection can be classified into three types: hyperacute, acute, and chronic.<ref name=":6">{{cite journal | vauthors = Moreau A, Varey E, Anegon I, Cuturi MC | title = Effector mechanisms of rejection | journal = Cold Spring Harbor Perspectives in Medicine | volume = 3 | issue = 11 | pages = a015461 | date = November 2013 | pmid = 24186491 | pmc = 3808773 | doi = 10.1101/cshperspect.a015461 }}</ref> These types are differentiated by how quickly the recipient's immune system is activated and the specific aspect or aspects of immunity involved.<ref name=":0">{{cite journal | vauthors = Moreau A, Varey E, Anegon I, Cuturi MC | title = Effector mechanisms of rejection | journal = Cold Spring Harbor Perspectives in Medicine | volume = 3 | issue = 11 | pages = a015461 | date = November 2013 | pmid = 24186491 | pmc = 3808773 | doi = 10.1101/cshperspect.a015461 }}</ref>


===Hyperacute rejection===
{{Main|Histocompatibility}}


'''Hyperacute rejection''' is a form of rejection that manifests itself in the minutes to hours following transplantation.<ref name=":1">{{cite book | vauthors = Chang YC | chapter = The surgical and immunosuppressive basis for infections in the pediatric solid organ transplant recipient |date=2021-01-01 | doi = 10.1016/B978-0-323-64198-2.00010-5 | title = Pediatric Transplant and Oncology Infectious Diseases |pages=1–9.e3 | veditors = Steinbach WJ, Green MD, Michaels MG, Danziger-Isakov LA |place=Philadelphia |publisher=Elsevier |language=en |isbn=978-0-323-64198-2 | s2cid = 228907807 }}</ref> It is caused by the presence of pre-existing [[Antibody|antibodies]] in the recipient that recognize [[antigen]]s in the donor organ.<ref>{{cite book | vauthors = Harmon WE | chapter = Chapter 41 - Pediatric Renal Transplantation |date=2010-01-01 | doi = 10.1016/B978-1-4377-0987-2.00041-8 | title = Chronic Kidney Disease, Dialysis, and Transplantation | edition = Third |pages=591–608 | veditors = Himmelfarb J, Sayegh MH |place=Philadelphia |publisher=W.B. Saunders |language=en |isbn=978-1-4377-0987-2 }}</ref> These antigens are located on the endothelial lining of blood vessels within the transplanted organ and, once antibodies bind, will lead to the rapid activation of the [[complement system]].<ref name=":2">{{cite book | chapter = Chapter 17 - Transplantation |date=2014-01-01 |doi = 10.1016/B978-0-12-385245-8.00017-0 | title = Primer to the Immune Response | edition = Second |pages=457–486 | veditors = Mak TW, Saunders ME, Jett BD | location = Boston |publisher=Academic Cell |language=en |isbn=978-0-12-385245-8 }}</ref> Irreversible damage via thrombosis and subsequent graft necrosis is to be expected.<ref>{{cite book | vauthors = Dharnidharka VR | chapter = 43 - Pediatric Renal Transplantation |date=2019-01-01 |doi = 10.1016/B978-0-323-52978-5.00043-4 | title = Chronic Kidney Disease, Dialysis, and Transplantation | edition = Fourth |pages=661–675.e7 | veditors = Himmelfarb J, Ikizler TA |place=Philadelphia |publisher=Elsevier |language=en |isbn=978-0-323-52978-5 | s2cid = 81475473 }}</ref> Tissue left implanted will fail to work and could lead to high fever and malaise as the immune system acts against foreign tissue.<ref name=":4">{{cite book | vauthors = Vitak K | chapter = Chapter 14 - Organ Transplantation |date=2014-01-01 | doi = 10.1016/B978-1-4557-2896-1.00014-7 | title = Acute Care Handbook for Physical Therapists | edition = Fourth |pages=335–356 | veditors = Paz JC, West MP |place=St. Louis |publisher=W.B. Saunders |language=en |isbn=978-1-4557-2896-1 }}</ref>
The first successful organ transplant, performed in 1954 by [[Joseph Murray]], involved identical twins, and so no rejection was observed. Otherwise, the number of mismatched gene variants, namely [[alleles]], encoding cell surface molecules called [[major histocompatibility complex]] (MHC), classes I and II, correlate with the rapidity and severity of transplant rejection. In humans MHC is also called [[human leukocyte antigen]] (HLA).


Though cytotoxic-crossmatch assay can predict rejection mediated by [[cellular immunity]], genetic-expression tests specific to the organ type to be transplanted, for instance [[AlloMap Molecular Expression Testing]], have a high negative predictive value. Transplanting only [[blood groups|ABO]]-compatible grafts (matching blood groups between donor and recipient) helps prevent rejection mediated by [[humoral immunity]].

=== ABO-incompatible transplants ===
{{main|ABO-incompatible transplantation}}
{{main|ABO-incompatible transplantation}}
Because very young children (generally under 12 months, but often as old as 24 months<ref name="west2009">ABO Incompatible Heart Transplantation in Young Infants. (2009, July 30). ABO Incompatible Heart Transplantation in Young Infants. American Society of Transplantation. Retrieved from http://www.myast.org/podcasts/abo-incompatible-heart-transplantation-young-infants</ref>) do not have a well-developed [[immune system]],<ref name="pmid21836514">{{cite journal|doi=10.1097/MOT.0b013e32834a97a5|pmid=21836514|year=2011|author1=West|first1=L. J.|title=ABO-incompatible hearts for infant transplantation|journal=Current opinion in organ transplantation|volume=16|issue=5|pages=548–54}}</ref> it is possible for them to receive organs from otherwise incompatible donors. This is known as ABO-incompatible (ABOi) transplantation. Graft survival and patient mortality is approximately the same between ABOi and ABO-compatible (ABOc) recipients.<ref name="pmid20308266">{{cite journal|last=Saczkowski|first=R|author2=Dacey, C |author3=Bernier, PL |title=Does ABO-incompatible and ABO-compatible neonatal heart transplant have equivalent survival?|journal=Interactive cardiovascular and thoracic surgery|date=Jun 2010|volume=10|issue=6|pages=1026–33|doi=10.1510/icvts.2009.229757|pmid=20308266}}</ref> While focus has been on infant heart transplants, the principles generally apply to other forms of solid organ transplantation.<ref name="west2009" />


Graft failure secondary to hyperacute rejection has significantly decreased in incidence as a result of improved pre-transplant screening for antibodies to donor tissues.<ref name=":1" /> While these preformed antibodies may result from prior transplants, prior blood transfusions, or pregnancy, hyperacute rejection is most commonly from antibodies to [[ABO blood group system|ABO blood group]] antigens.<ref name=":2" /> Consequently, transplants between individuals with differing ABO blood types is generally avoided though may be pursued in very young children (generally under 12 months, but often as old as 24 months)<ref name="West_2001">{{cite journal | vauthors = West LJ, Pollock-Barziv SM, Dipchand AI, Lee KJ, Cardella CJ, Benson LN, Rebeyka IM, Coles JG | title = ABO-incompatible heart transplantation in infants | journal = The New England Journal of Medicine | volume = 344 | issue = 11 | pages = 793–800 | date = March 2001 | pmid = 11248154 | doi = 10.1056/NEJM200103153441102 | doi-access = free }}</ref> who do not have fully developed immune systems.<ref name="pmid21836514">{{cite journal | vauthors = West LJ | title = ABO-incompatible hearts for infant transplantation | journal = Current Opinion in Organ Transplantation | volume = 16 | issue = 5 | pages = 548–554 | date = October 2011 | pmid = 21836514 | doi = 10.1097/MOT.0b013e32834a97a5 | s2cid = 26070409 }}</ref> Shortages of organs and the morbidity and mortality associated with being on transplant waitlists has also increased interest in ABO-incompatible transplantation in older children and adults.<ref>{{cite journal | vauthors = Subramanian V, Ramachandran S, Klein C, Wellen JR, Shenoy S, Chapman WC, Mohanakumar T | title = ABO-incompatible organ transplantation | journal = International Journal of Immunogenetics | volume = 39 | issue = 4 | pages = 282–290 | date = August 2012 | pmid = 22339811 | doi = 10.1111/j.1744-313x.2012.01101.x | s2cid = 41947505 | doi-access = free }}</ref>
The most important factors are that the recipient not have produced [[isohemagglutinin]]s, and that they have low levels of T cell-independent [[antigen]]s.<ref name="pmid21836514" /><ref name="pmid15033856">{{cite journal|last=Burch|first=M|author2=Aurora, P |title=Current status of paediatric heart, lung, and heart-lung transplantation|journal=Archives of Disease in Childhood|date=Apr 2004|volume=89|issue=4|pages=386–389|pmid=15033856|pmc=1719883|doi=10.1136/adc.2002.017186}}</ref> UNOS regulations allow for ABOi transplantation in children under two years of age if isohemagglutinin titers are 1:4 or below,<ref name="unos_policy_3.7">United Network for Organ Sharing. (2013, January 31). OPTN Policy 3.7 - Allocation of Thoracic Organs. Retrieved from http://optn.transplant.hrsa.gov/policiesAndBylaws/policies.asp</ref><ref name="pmid23305695">{{cite journal|last=Urschel|first=S|author2=Larsen, IM; Kirk, R; Flett, J; Burch, M; Shaw, N; Birnbaum, J; Netz, H; Pahl, E; Matthews, KL; Chinnock, R; Johnston, JK; Derkatz, K; West, LJ|title=ABO-incompatible heart transplantation in early childhood: an international multicenter study of clinical experiences and limits|journal=The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation|date=Mar 2013|volume=32|issue=3|pages=285–92|doi=10.1016/j.healun.2012.11.022|pmid=23305695}}</ref> and if there is no matching ABOc recipient.<ref name="unos_policy_3.7" /><ref name="pmid23305695" /><ref name="pmid20404257">{{cite journal|last=Almond|first=CS|author2=Gauvreau, K |author3=Thiagarajan, RR |author4=Piercey, GE |author5=Blume, ED |author6=Smoot, LB |author7=Fynn-Thompson, F |author8= Singh, TP |title=Impact of ABO-incompatible listing on wait-list outcomes among infants listed for heart transplantation in the United States: a propensity analysis|journal=Circulation|date=May 4, 2010|volume=121|issue=17|pages=1926–33|doi=10.1161/CIRCULATIONAHA.109.885756|pmid=20404257}}</ref> Studies have shown that the period under which a recipient may undergo ABOi transplantation may be prolonged by exposure to nonself A and B antigens.<ref name="pmid15502841">{{cite journal|last=Fan|first=X|author2=Ang, A |author3=Pollock-Barziv, SM |author4=Dipchand, AI |author5=Ruiz, P |author6=Wilson, G |author7=Platt, JL |author8= West, LJ |title=Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation|journal=Nature Medicine|date=Nov 2004|volume=10|issue=11|pages=1227–33|doi=10.1038/nm1126|pmid=15502841}}</ref> Furthermore, should the recipient (for example, type B-positive with a type AB-positive graft) require eventual retransplantation, the recipient may receive a new organ of either blood type.<ref name="west2009" /><ref name="pmid23305695" />


===Acute rejection===
Limited success has been achieved in ABO-incompatible heart transplants in adults,<ref name="pmid23107062">{{cite journal|last=Tydén|first=G|author2=Hagerman, I; Grinnemo, KH; Svenarud, P; van der Linden, J; Kumlien, G; Wernerson, A|title=Intentional ABO-incompatible heart transplantation: a case report of 2 adult patients|journal=The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation|date=Dec 2012|volume=31|issue=12|pages=1307–10|doi=10.1016/j.healun.2012.09.011|pmid=23107062}}</ref> though this requires that the adult recipients have low levels of anti-A or anti-B antibodies.<ref name="pmid23107062" /> Kidney transplantation is more successful, with similar long-term graft survival rates to ABOc transplants.<ref name="pmid23305695" />


{{Main|Histocompatibility}}
==Immunologic mechanisms of rejection==


'''Acute rejection''' is a category of rejection that occurs on the timescale of weeks to months, with most episodes occurring within the first 3 months to 1 year after transplantation.<ref name=":2" /><ref name=":4" /> Unlike hyperacute rejection, acute rejection is thought to arise from two distinct immunological mechanisms as [[lymphocyte]]s, a subset of white blood cells, begin to recognize antigens on transplanted organ/graft.<ref name=":10">{{cite book | vauthors = Justiz Vaillant AA, Mohseni M | chapter = Chronic Transplantation Rejection |date=2022 | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK535435/ | title = StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30571056 |access-date=2022-03-16 }}</ref> This recognition occurs due to the [[major histocompatibility complex]] (MHC), which are proteins on cell surface that are presented to the T-cell receptor found on [[T cell|T-cells]].<ref name=":3">{{cite web |title=Human Leukocyte Antigen (HLA) System - Immunology; Allergic Disorders |url=https://www.merckmanuals.com/professional/immunology-allergic-disorders/biology-of-the-immune-system/human-leukocyte-antigen-hla-system |access-date=30 September 2020 |website=Merck Manuals Professional Edition |publisher=Merck & Co. |language=en |vauthors=Delves PJ}}</ref> In humans, this is known as the human leukocyte antigen (HLA) system<ref name=":3" /> and over 17,000 HLA alleles or genetic variants have been described such that it is extremely uncommon for any two people to have identical alleles.<ref>{{cite book | vauthors = Frenet EM, Scaradavou A | chapter = Chapter 32 - Human Leukocyte Antigens |date=2019-01-01 |doi = 10.1016/B978-0-12-813726-0.00032-5 | title = Transfusion Medicine and Hemostasis | edition = Third |pages=191–197 | veditors = Shaz BH, Hillyer CD, Gil MR |publisher = Elsevier |language=en |isbn=978-0-12-813726-0 | s2cid = 91582896 | url = https://intech-files.s3.amazonaws.com/a043Y00000s2SI4QAM/0014247_Authors_Book%20%282023-06-23%2009%3A48%3A45%29.pdf }}</ref> Other non-HLA proteins, known as minor histocompatibility antigens, do exist but generally are unable to cause acute rejection in and of themselves unless a multitude of non-HLA proteins are mismatched.<ref name=":5">{{cite book | vauthors = Menon MC, Cravedi P, El Salem F | chapter = Chapter 32 - Acute Cellular Rejection |date=2017-01-01 | doi = 10.1016/B978-0-12-801734-0.00032-1 | title = Kidney Transplantation, Bioengineering and Regeneration |pages=461–474 | veditors = Orlando G, Remuzzi G, Williams DF |publisher=Academic Press |language=en |isbn=978-0-12-801734-0 }}</ref> As such, HLA matching (in addition to matching ABO groups) is critical in preventing acute rejection.<ref name=":9">{{cite book | vauthors = Justiz Vaillant AA, Misra S, Fitzgerald BM | chapter = Acute Transplantation Rejection |date=2022 | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK535410/ | title = StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30571031 |access-date=2022-03-16 }}</ref>
Rejection is an [[adaptive immune response]] via [[cellular immunity]] (mediated by killer T cells inducing apoptosis of target cells) as well as [[humoral immunity]] (mediated by [[plasma cells|activated B cells]] secreting [[antibody]] molecules), though the action is joined by components of [[innate immune response]] ([[phagocytes]] and soluble immune proteins). Different types of transplanted tissues tend to favor different balances of rejection mechanisms.


This process of recognition by T-cells can happen directly or indirectly and lead to acute cellular and acute humoral rejection respectively.<ref name=":2" /> Direct allorecognition is a phenomenon within transplant immunology where the [[dendritic cell]]s, which are the body's [[antigen-presenting cells]] (APCs), migrate from ''donor'' tissue to [[lymphoid tissue]] ([[lymphoid follicles]] and [[lymph nodes]]) in the ''recipient'' and present their MHC peptides to recipient lymphocytes.<ref name=":8">{{cite journal | vauthors = Boardman DA, Jacob J, Smyth LA, Lombardi G, Lechler RI | title = What Is Direct Allorecognition? | journal = Current Transplantation Reports | volume = 3 | issue = 4 | pages = 275–283 | date = 2016 | pmid = 27909647 | pmc = 5107184 | doi = 10.1007/s40472-016-0115-8 }}</ref> In comparison, indirect allorecognition is more analogous to how foreign antigens are recognized by the immune system.<ref name=":7">{{cite journal | vauthors = Ingulli E | title = Mechanism of cellular rejection in transplantation | journal = Pediatric Nephrology | volume = 25 | issue = 1 | pages = 61–74 | date = January 2010 | pmid = 21476231 | pmc = 2778785 | doi = 10.1007/s00467-008-1020-x }}</ref> Dendritic cells of the ''recipient'' come across peptides from donor tissue whether in circulation, lymphoid tissue, or in donor tissue itself.<ref name=":7" /> Since not the result of direct antigen presentation, these may not necessarily be intact MHC molecules but instead other proteins that are deemed different enough from recipient may engender a response.<ref name=":7" /> This process leads to the priming of T-cells to respond to the peptides secondarily going forward.<ref name=":6" /> A third semi-direct pathway has been described in which recipient APCs present fully intact donor MHCs,<ref name=":8" /> yet its relative contribution to acute rejection is not as well understood.<ref name=":5" />
===Immunization===

An animal's exposure to the antigens of a different member of the same or similar species is ''allostimulation'', and the tissue is ''allogenic''. Transplanted organs are often acquired from a [[cadaver]] (usually a host who had succumbed to trauma), whose tissues had already sustained [[ischemia]] or [[inflammation]].

[[Dendritic cells]] (DCs), which are the primary [[antigen-presenting cells]] (APCs), of the donor tissue migrate to the recipient's peripheral [[lymphoid tissue]] ([[lymphoid follicles]] and [[lymph nodes]]), and present the donor's ''self'' [[peptides]] to the recipient's [[lymphocytes]] (immune cells residing in lymphoid tissues). Lymphocytes include two classes that enact [[adaptive immunity]], also called specific immunity. Lymphocytes of specific immunity [[T cell]]s—including the subclasses [[helper T cell]]s and [[killer T cell]]s—and [[B cell]]s.

The recipient's helper T cells coordinate specific immunity directed at the donor's ''self'' peptides or at the donor's [[Major histocompatibility complex]] molecules, or at both.

===Immune memory===

When memory helper T cells' [[CD4]] receptors bind to the [[MHC class II]] molecules which are expressed on the surfaces of the target cells of the graft tissue, the memory helper T cells' [[T cell receptor]]s (TCRs) can recognize their target antigen that is presented by the MHC class II molecules. The memory helper T cell subsequently produces clones that, as effector cells, secrete immune signalling molecules ([[cytokines]]) in approximately the cytokine balance that had prevailed at the memory helper T cell's priming to memorize the antigen. As the priming event in this instance occurred amid inflammation, the immune memory is pro-inflammatory.

===Cellular immunity===

As a cell is indicated by the prefix ''cyto'', a cytotoxic influence destroys the cell. Alloreactive [[killer T cells]], also called cytotoxic T lymphocytes (CTLs), have [[CD8]] receptors that dock to the transplanted tissue's MHC class I molecules,which display the donor's self peptides. (In the living donor, such presentation of ''self'' antigens helped maintain ''self'' tolerance.) Thereupon, the [[T cell receptor]]s (TCRs) of the killer T cells recognize their matching [[epitope]], and trigger the target cell's [[programmed cell death]] by [[apoptosis]].

===Humoral immunity===

Developed through an earlier ''primary exposure'' that primed specific immunity to the ''nonself'' antigen, a transplant recipient can have specific antibody crossreacting with the donor tissue upon the transplant event, a ''secondary exposure''. This is typical after earlier mismatching among A/B/O [[blood types]] during blood transfusion. At this secondary exposure, these crossreactive antibody molecules interact with aspects of [[innate immunity]]—soluble immune proteins called [[complement system|complement]] and innate immune cells called [[phagocytes]]—which inflames and destroys the transplanted tissue.

====Antibody====

Secreted by an activated B cell, then called [[plasma cell]], an antibody molecule is a soluble immunoglobulin (Ig) whose basic unit is shaped like the letter ''Y'': the two arms are the [[Fab regions]], while the single stalk is the [[Fc region]]. Each of the two tips of Fab region is the [[paratope]], which binds a matching molecular sequence and its 3D shape (conformation), altogether called [[epitope]], within the target antigen.

====Opsonization====

The IgG's Fc region also enables [[opsonization]] by a [[phagocyte]], a process by which the [[Fc receptor]] on the phagocyte—such as [[neutrophils]] in blood and [[macrophages]] in tissues—binds the antibody molecule's FC stalk, and the phagocyte exhibits enhanced uptake of the antigen, attached to the antibody molecule's Fab region.

====Complement cascade====

When the paratope of Ig class ''gamma'' (IgG) binds its matching epitope, IgG's Fc region conformationally shifts and can host a complement protein, initiating the [[complement cascade]] that terminates by punching a hole in a cell membrane. With many holes so punched, fluid rushes into the cell and ruptures it.

Cell debris can be recognized as [[DAMPs|damage associated molecular patterns]] (DAMPs) by [[pattern recognition receptors]] (PRRs), such as [[Toll-like receptors]] (TLRs), on membranes of [[phagocytes]], which thereupon secrete proinflammatory [[cytokine]]s, recruiting more phagocytes to traffic to the area by sensing the [[concentration gradient]] of the secreted cytokines ([[chemotaxis]]).

{|class="wikitable" style="text-align:center"
!Tissue !! Mechanism
|-
|Blood || [[Antibodies]] (isohaemagglutinins)
|-
|Kidney || Antibodies, [[cell-mediated immunity]] (CMI)
|-
|Heart || Antibodies, CMI
|-
|Skin || CMI
|-
|Bonemarrow || CMI
|-
|Cornea || Usually accepted unless vascularised: CMI
|}

==Medical categories of rejection==

===Hyperacute rejection===

Initiated by preexisting [[humoral immunity]], ''hyperacute rejection'' manifests within minutes after transplant, and if tissue is left implanted brings [[systemic inflammatory response syndrome]]. Of high risk in [[kidney]] transplants is rapid clumping, namely [[agglutination (biology)|agglutination]], of [[red blood cells]] (RBCs or erythrocytes), as an antibody molecule binds multiple target cells at once.

While kidneys can routinely be obtained from human donors, most organs are in short supply leading to consideration of xenotransplants from other species. Pigs are especially likely sources for xenotransplants, chosen for the anatomical and physiological characteristics they share with humans.<ref name="pmid19998476">{{cite journal|last=Klymiuk|first=N|author2=Aigner, B |author3=Brem, G |author4= Wolf, E |title=Genetic modification of pigs as organ donors for xenotransplantation|journal=Molecular reproduction and development|date=Mar 2010|volume=77|issue=3|pages=209–21|pmid=19998476|doi=10.1002/mrd.21127}}</ref> However, the sugar [[galactose-alpha-1,3-galactose]] (αGal) has been implicated as a major factor in hyperacute rejection in [[xenotransplantation]]. Unlike virtually all other mammals, humans and other primates do not make αGal, and in fact recognize it as an antigen.<ref name="pmid16266320">{{cite journal|last=Galili|first=U|title=The alpha-gal epitope and the anti-Gal antibody in xenotransplantation and in cancer immunotherapy|journal=Immunology and cell biology|date=Dec 2005|volume=83|issue=6|pages=674–86|doi=10.1111/j.1440-1711.2005.01366.x|pmid=16266320}}</ref> During transplantation, xenoreactive natural antibodies recognize αGal on the graft endothelium as an antigen, and the resulting complement-mediated immune response leads to a rejection of the transplant.<ref name="pmid10700475">{{cite journal|last=Candinas|first=D|author2=Adams, DH |title=Xenotransplantation: postponed by a millennium?|journal=QJM : monthly journal of the Association of Physicians|date=Feb 2000|volume=93|issue=2|pages=63–6|doi=10.1093/qjmed/93.2.63|pmid=10700475}}</ref>

===Acute rejection===


Acute cellular rejection occurs following direct allorecognition of mismatched donor MHC by [[Cytotoxic T cell|cytotoxic T-cells]] that begin to secrete [[cytokine]]s to recruit more lymphocytes as well as cause apoptosis or cell death directly.<ref name=":1" /><ref name=":2" /> The greater the difference in MHC between donor and recipient, the more cytotoxic T-cells are recruited to damage the graft,<ref name=":2" /> which may be seen via biopsy in solid organ transplants, with increased lymphocyte infiltration indicative of more severe acute cellular rejection.<ref name=":5" /> Acute humoral rejection is a process usually initiated by indirect allorecognition arising from recipient [[T helper cell|helper T-cells]].<ref name=":2" /> These helper T-cells have a crucial role in the development of B-cells that can create donor-specific antibodies.<ref name=":1" /> The antibodies deposit themselves within the donor graft and lead to activation of the complement cascade alongside antibody-mediated cytotoxicity with [[neutrophil]]s, a type of white blood cell separate from lymphocytes, predominantly infiltrating into tissues.<ref name=":2" />
Developing with formation of [[cellular immunity]], ''acute rejection'' occurs to some degree in all transplants, except between identical twins, unless immunosuppression is achieved (usually through drugs). Acute rejection begins as early as one week after transplant, the risk being highest in the first three months, though it can occur months to years later. Highly [[vascular]] tissues such as kidney or liver often host the earliest signs—particularly at [[endothelium|endothelial cells]] lining blood vessels—though it eventually occurs in roughly 10 to 30% of liver transplants, and 10 to 20% of kidney transplants. A single episode of acute rejection can be recognized and promptly treated, usually preventing organ failure, but recurrent episodes lead to ''chronic rejection''. It is believed that the process of acute rejection is mediated by the cell mediated pathway, specifically by mononuclear macrophages and T-lymphocytes.


Barring genetically identical twins, acute rejection is to be expected to some degree.<ref name=":9" /> Rates of clinically significant acute rejection that could endanger transplant have decreased significantly with the development of immunosuppressive regimens. Using kidney transplants as an example, rates of acute rejection have declined from >50% in the 1970s to 10-20%.<ref>{{cite journal | vauthors = Clayton PA, McDonald SP, Russ GR, Chadban SJ | title = Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients: An ANZDATA Analysis | journal = Journal of the American Society of Nephrology | volume = 30 | issue = 9 | pages = 1697–1707 | date = September 2019 | pmid = 31308074 | pmc = 6727270 | doi = 10.1681/ASN.2018111101 }}</ref> Singular episodes of acute rejection, when promptly treated, should not compromise transplant; however, repeated episodes may lead to chronic rejection.<ref name=":9" />
===Chronic rejection===
===Chronic rejection===
[[Image:Transplant glomerulopathy - very high mag.jpg| thumb| [[Micrograph]] showing a [[glomerulus]] with changes characteristic of a transplant glomerulopathy. [[Transplant glomerulopathy]] is considered a form of chronic antibody-mediated rejection. [[PAS stain]].]]
[[Image:Transplant glomerulopathy - very high mag.jpg| thumb| [[Micrograph]] showing a [[glomerulus]] with changes characteristic of a transplant glomerulopathy. [[Transplant glomerulopathy]] is considered a form of chronic antibody-mediated rejection. [[PAS stain]].]]
'''Chronic rejection''' is an insidious form of rejection that leads to graft destruction over the course of months, but most often years after tissue transplantation.<ref name=":10" /> The mechanism for chronic rejection is yet to be fully understood, but it is known that prior acute rejection episodes are the main clinical predictor for the development of chronic rejection.<ref name=":2" /> In particular, the incidence increases following severe or persistent acute rejection, whereas acute rejection episodes with return to function back to baseline do not have major effects on graft survival.<ref name=":11">{{cite book | vauthors = Gautreaux MD | chapter = Chapter 17 - Histocompatibility Testing in the Transplant Setting |date=2017-01-01 | title = Kidney Transplantation, Bioengineering and Regeneration |pages=223–234 | veditors = Orlando G, Remuzzi G, Williams DF |publisher=Academic Press |language=en |doi=10.1016/b978-0-12-801734-0.00017-5 |isbn=978-0-12-801734-0 }}</ref><ref>{{cite book | vauthors = Srinivas TR, Schold JD, Meier-Kriesche HU | chapter = Chapter 105 - Outcomes of Renal Transplantation |date=2010-01-01 | title = Comprehensive Clinical Nephrology |pages=1222–1231 | veditors = Floege J, Johnson RJ, Feehally J |place=Philadelphia |publisher=Mosby |language=en |doi=10.1016/b978-0-323-05876-6.00105-2 |isbn=978-0-323-05876-6 | edition = Fourth }}</ref> Chronic rejection is generally thought of as being related to either vascular damage or parenchymal damage with subsequent fibrosis.<ref>{{cite book | vauthors = Dharnidharka VR | chapter = Chapter 43 - Pediatric Renal Transplantation |date=2019-01-01 |doi = 10.1016/B978-0-323-52978-5.00043-4 | title = Chronic Kidney Disease, Dialysis, and Transplantation | edition = Fourth |pages=661–675.e7 | veditors = Himmelfarb J, Ikizler TA |place=Philadelphia |publisher=Elsevier |language=en |isbn=978-0-323-52978-5 | s2cid = 81475473 }}</ref> While it is unknown the exact contribution of the immune system in these processes, the indirect pathway of allorecognition and the associated antibody formation seems to be especially involved.<ref name=":2" />
The term ''chronic rejection'' initially described long-term loss of function in transplanted organs via [[fibrosis]] of the transplanted tissue's blood vessels. This is now ''chronic allograft vasculopathy'', however, leaving ''chronic rejection'' referring to rejection due to more patent aspects of immunity.


Chronic rejection explains long-term morbidity in most lung-transplant recipients,<ref name="pmid15667618">{{cite journal|last=Jaramillo|first=A|author2=Fernández, FG |author3=Kuo, EY |author4=Trulock, EP |author5=Patterson, GA |author6= Mohanakumar, T |title=Immune mechanisms in the pathogenesis of bronchiolitis obliterans syndrome after lung transplantation|journal=Pediatric transplantation|date=Feb 2005|volume=9|issue=1|pages=84–93|pmid=15667618|doi=10.1111/j.1399-3046.2004.00270.x}}</ref><ref name="pmid14621118">{{cite journal|last=Lau|first=CL|author2=Patterson, GA |title=Current status of lung transplantation|journal=The European respiratory journal. Supplement|date=Nov 2003|volume=47|pages=57s–64s|pmid=14621118}}</ref> the median survival roughly 4.7 years, about half the span versus other major organ transplants.<ref>http://www.OPTN.org</ref> In histopathology the condition is ''bronchiolitis obliterans'', which clinically presents as progressive airflow obstruction, often involving [[dyspnea]] and [[coughing]], and the patient eventually succumbs to [[pulmonary insufficiency]] or secondary acute infection.
Chronic rejection has widely varied effects on different organs. At 5 years post-transplant, 80% of lung transplants, 60% of heart transplants and 50% of kidney transplants are affected, while liver transplants are only affected 10% of the time.<ref name=":11" /> Therefore, chronic rejection explains long-term morbidity in most lung-transplant recipients,<ref name="pmid15667618">{{cite journal | vauthors = Jaramillo A, Fernández FG, Kuo EY, Trulock EP, Patterson GA, Mohanakumar T | title = Immune mechanisms in the pathogenesis of bronchiolitis obliterans syndrome after lung transplantation | journal = Pediatric Transplantation | volume = 9 | issue = 1 | pages = 84–93 | date = February 2005 | pmid = 15667618 | doi = 10.1111/j.1399-3046.2004.00270.x | s2cid = 25841425 }}</ref><ref name="pmid14621118">{{cite journal | vauthors = Lau CL, Patterson GA | title = Current status of lung transplantation | journal = The European Respiratory Journal. Supplement | volume = 47 | pages = 57s–64s | date = November 2003 | pmid = 14621118 | doi = 10.1183/09031936.03.00022103 | doi-access = free }}</ref> the median survival roughly 4.7 years, about half the span versus other major organ transplants.<ref>{{cite web | title = Organ Procurement and Transplantation Network | work = U.S. Department of Health & Human Services | url = http://optn.transplant.hrsa.gov/ }}</ref> Airflow obstruction not ascribable to other cause is labeled [[bronchiolitis obliterans]] [[syndrome]] (BOS), confirmed by a persistent drop—three or more weeks—in ''forced expiratory volume'' (FEV<sub>1</sub>) by at least 20%.<ref name="pmid17347496">{{cite journal |display-authors=6 |vauthors=Lama VN, Murray S, Lonigro RJ, Toews GB, Chang A, Lau C, Flint A, Chan KM, Martinez FJ |date=June 2007 |title=Course of FEV(1) after onset of bronchiolitis obliterans syndrome in lung transplant recipients |journal=American Journal of Respiratory and Critical Care Medicine |volume=175 |issue=11 |pages=1192–1198 |doi=10.1164/rccm.200609-1344OC |pmc=1899272 |pmid=17347496}}</ref> First noted is infiltration by [[lymphocytes]], followed by [[epithelium|epithelial cell]] injury, then inflammatory lesions and recruitment of [[fibroblasts]] and [[myofibroblasts]], which proliferate and secrete proteins forming scar tissue.<ref name="pmid16799090">{{cite journal |vauthors=Nicod LP |date=July 2006 |title=Mechanisms of airway obliteration after lung transplantation |journal=Proceedings of the American Thoracic Society |volume=3 |issue=5 |pages=444–449 |doi=10.1513/pats.200601-007AW |pmid=16799090}}</ref> A similar phenomenon can be seen with liver transplant wherein fibrosis leads to jaundice secondary to the destruction of bile ducts within the liver, also known as vanishing bile duct syndrome.<ref>{{cite book | vauthors = Hübscher SG, Clouston AD | chapter = Chapter 15 - Transplantation pathology |date= January 2012 | doi =10.1016/B978-0-7020-3398-8.00015-5 | title = MacSween's Pathology of the Liver |pages=853–933 | veditors = Burt AD, Portmann BC, Ferrell LD |place=Edinburgh |publisher=Churchill Livingstone |language=en |isbn=978-0-7020-3398-8 | edition = Sixth }}</ref>

Airflow obstruction not ascribable to other cause is labeled [[bronchiolitis obliterans]] [[syndrome]] (BOS), confirmed by a persistent drop—three or more weeks—in ''forced expiratory volume'' (FEV<sub>1</sub>) by at least 20%.<ref name="pmid17347496">{{cite journal|last=Lama|first=VN|author2=Murray, S |author3=Lonigro, RJ |author4=Toews, GB |author5=Chang, A |author6=Lau, C |author7=Flint, A |author8=Chan, KM |author9= Martinez, FJ |title=Course of FEV(1) after onset of bronchiolitis obliterans syndrome in lung transplant recipients|journal=American Journal of Respiratory and Critical Care Medicine|date=Jun 1, 2007|volume=175|issue=11|pages=1192–8|pmid=17347496|pmc=1899272|doi=10.1164/rccm.200609-1344OC}}</ref> BOS is seen in over 50% of lung-transplant recipients by 5 years, and in over 80% by ten years. First noted is infiltration by [[lymphocytes]], followed by [[epithelium|epithelial cell]] injury, then inflammatory lesions and recruitment of [[fibroblasts]] and [[myofibroblasts]], which proliferate and secrete proteins forming scar tissue.<ref name="pmid16799090">{{cite journal|last=Nicod|first=LP|title=Mechanisms of airway obliteration after lung transplantation|journal=Proceedings of the American Thoracic Society|date=Jul 2006|volume=3|issue=5|pages=444–9|doi=10.1513/pats.200601-007AW|pmid=16799090}}</ref> Generally thought unpredictable, BOS progression varies widely: lung function may suddenly fall but stabilize for years, or rapidly progress to death within a few months. Risk factors include prior acute rejection episodes, [[gastroesophageal reflux disease]], acute infections, particular age groups, HLA mis-matching, [[lymphocytic bronchiolitis]], and graft dysfunction (e.g., airway ischemia).<ref name="pmid19131536">{{cite journal|last=Belperio|first=JA|author2=Weigt, SS |author3=Fishbein, MC |author4= Lynch JP, 3rd |title=Chronic lung allograft rejection: mechanisms and therapy|journal=Proceedings of the American Thoracic Society|date=Jan 15, 2009|volume=6|issue=1|pages=108–21|doi=10.1513/pats.200807-073GO|pmid=19131536}}</ref>


== Rejection due to non-adherence ==
== Rejection due to non-adherence ==
One principal reason for transplant rejection is non-adherence to prescribed immunosuppressant regimens. This is particularly the case with adolescent recipients,<ref name="pmid22248250">{{cite journal|last=Dobbels|first=F|author2=Hames, A |author3=Aujoulat, I |author4=Heaton, N |author5= Samyn, M |title=Should we retransplant a patient who is non-adherent? A literature review and critical reflection|journal=Pediatric transplantation|date=Feb 2012|volume=16|issue=1|pages=4–11|doi=10.1111/j.1399-3046.2011.01633.x|pmid=22248250}}</ref> with non-adherence rates near 50% in some instances.<ref name="pmid22248250" />
One principal reason for transplant rejection is non-adherence to prescribed immunosuppressant regimens. This is particularly the case with adolescent recipients,<ref name="pmid22248250">{{cite journal | vauthors = Dobbels F, Hames A, Aujoulat I, Heaton N, Samyn M | title = Should we retransplant a patient who is non-adherent? A literature review and critical reflection | journal = Pediatric Transplantation | volume = 16 | issue = 1 | pages = 4–11 | date = February 2012 | pmid = 22248250 | doi = 10.1111/j.1399-3046.2011.01633.x | s2cid = 1895827 | url = https://lirias.kuleuven.be/handle/123456789/363151 }}</ref> with non-adherence rates near 50% in some instances.<ref name="pmid22248250" />

A pilot study conducted by Michael O. Killian PhD from Florida State University and Dr. Dipankar Gupta from University of Florida published in April 2022 in ''Pediatric Transplantation'' <ref>{{Cite journal |last1=Killian |first1=Michael O. |last2=Clifford |first2=Stephanie |last3=Lustria |first3=Mia Liza A. |last4=Skivington |first4=Gage L. |last5=Gupta |first5=Dipankar |date=2022-04-18 |title=Directly observed therapy to promote medication adherence in adolescent heart transplant recipients |journal=Pediatric Transplantation |volume=26 |issue=5 |pages=e14288 |language=en |doi=10.1111/petr.14288 |pmid=35436376 |s2cid=248242427 |issn=1397-3142|doi-access=free }}</ref> studied the acceptability and feasibility of an asynchronous directly observed therapy mobile health application among adolescent heart transplant recipients. Patients in the study utilized emocha Health's digital medication adherence program which included asynchronous video messages and chat messages exchanged with a care team. Patients completing the study achieved a 90.1% adherence rate. The researchers noted that further randomized trials are required to confirm the initial findings. However, the results were very promising considering few options exist to support pediatric patients in taking their medications.{{cn|date=May 2024}}


==Rejection detection==
==Rejection detection==
Diagnosis of acute rejection relies on clinical data—patient signs and symptoms but also calls on laboratory data such as [[Peripheral blood cell|blood]] or even tissue [[biopsy]]. The laboratory pathologist generally seeks three main [[histology|histological]] signs: (1) infiltrating [[T cells]], perhaps accompanied by infiltrating [[eosinophils]], [[plasma cells]], and [[neutrophils]], particularly in telltale ratios, (2) structural compromise of tissue anatomy, varying by tissue type transplanted, and (3) injury to blood vessels. Tissue biopsy is restricted, however, by sampling limitations and risks/complications of the invasive procedure.<ref>{{cite web | url = https://www.mayoclinic.org/tests-procedures/kidney-biopsy/basics/risks/prc-20018979 | title = Kidney biopsy:risks | publisher = The Johns Hopkins University | work = Johns Hopkins Medicine }}</ref><ref>{{ClinicalTrialsGov|NCT00351559|IMAGE: A Comparison of AlloMap Molecular Testing and Traditional Biopsy-based Surveillance for Heart Transplant Rejection}}</ref><ref>{{cite web | url = https://www.hopkinsmedicine.org/healthlibrary/test_procedures/pulmonary/lung_biopsy_92,P07750 | title = Lung biopsy:risks | publisher = The Johns Hopkins University | work = Johns Hopkins Medicine | date = 8 August 2021 }}</ref> Cellular [[magnetic resonance imaging]] (MRI) of immune cells [[radiolabeling|radiolabeled]] ''in vivo'' might—similarly to [[Gene expression profiling|Gene Expression Profiling (GEP)]]—offer noninvasive testing.<ref name="pmid21305593">{{cite journal | vauthors = Hitchens TK, Ye Q, Eytan DF, Janjic JM, Ahrens ET, Ho C | title = 19F MRI detection of acute allograft rejection with in vivo perfluorocarbon labeling of immune cells | journal = Magnetic Resonance in Medicine | volume = 65 | issue = 4 | pages = 1144–1153 | date = April 2011 | pmid = 21305593 | pmc = 3135171 | doi = 10.1002/mrm.22702 }}</ref><ref>{{cite journal | vauthors = Gheith OA | title = Gene expression profiling in organ transplantation | journal = International Journal of Nephrology | volume = 2011 | pages = 180201 | year = 2011 | pmid = 21845224 | pmc = 3154482 | doi = 10.4061/2011/180201 | doi-access = free }}</ref>

Diagnosis of acute rejection relies on clinical data—patient signs and symptoms—but also calls on laboratory data such as tissue [[biopsy]]. The laboratory pathologist generally seeks three main [[histology|histological]] signs: (1) infiltrating [[T cells]], perhaps accompanied by infiltrating [[eosinophils]], [[plasma cells]], and [[neutrophils]], particularly in telltale ratios, (2) structural compromise of tissue anatomy, varying by tissue type transplanted, and (3) injury to blood vessels. Tissue biopsy is restricted, however, by sampling limitations and risks/complications of the invasive procedure. Cellular [[magnetic resonance imaging]] (MRI) of immune cells [[radiolabeling|radiolabeled]] ''in vivo'' might offer noninvasive testing.<ref name="pmid21305593">{{cite journal|last=Hitchens|first=TK|author2=Ye, Q |author3=Eytan, DF |author4=Janjic, JM |author5=Ahrens, ET |author6= Ho, C |title=19F MRI detection of acute allograft rejection with in vivo perfluorocarbon labeling of immune cells|journal=Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine|date=Apr 2011|volume=65|issue=4|pages=1144–53|doi=10.1002/mrm.22702|pmid=21305593|pmc=3135171}}</ref>


==Rejection treatment==
==Rejection treatment==
{{More citations needed section|date=June 2020}}

'''Hyperacute rejection''' manifests severely and within minutes, and so treatment is immediate: removal of the tissue. '''Chronic rejection''' is generally considered irreversible and poorly amenable to treatment—only retransplant generally indicated if feasible—though inhaled [[ciclosporin]] is being investigated to delay or prevent chronic rejection of lung transplants. '''Acute rejection''' is treated with one or several of a few strategies.
Hyperacute rejection manifests severely and within minutes, and so treatment is immediate: removal of the tissue. Acute rejection is treated with one or several of a few strategies. Despite treatment, rejection remains a major cause of transplant failure.<ref>{{cite journal |display-authors=6 |vauthors=Naesens M, Kuypers DR, De Vusser K, Evenepoel P, Claes K, Bammens B, Meijers B, Sprangers B, Pirenne J, Monbaliu D, Jochmans I, Lerut E |date=August 2014 |title=The histology of kidney transplant failure: a long-term follow-up study |journal=Transplantation |volume=98 |issue=4 |pages=427–435 |doi=10.1097/TP.0000000000000183 |pmid=25243513 |s2cid=20703626|doi-access=free }}</ref> Chronic rejection is generally considered irreversible and poorly amenable to treatment—only retransplant generally indicated if feasible—though inhaled [[ciclosporin]] is being investigated to delay or prevent chronic rejection of lung transplants.


===Immunosuppressive therapy===
===Immunosuppressive therapy===


A short course of high-dose [[corticosteroids]] can be applied, and repeated. ''Triple therapy'' adds a [[calcineurin inhibitor]] and an [[anti-proliferative agent]]. Where calcineurin inhibitors or steroids are contraindicated, [[mTOR|mTOR inhibitors]] are used.
A short course of high-dose [[corticosteroids]] can be applied, and repeated. ''Triple therapy'' adds a [[calcineurin inhibitor]] and an [[anti-proliferative agent]]. Where calcineurin inhibitors or steroids are contraindicated, [[mTOR|mTOR inhibitors]] are used.


'''Immunosuppressive drugs''':
'''Immunosuppressive drugs''':

* [[Corticosteroids]]
* [[Corticosteroids]]
** [[Prednisolone]]
** [[Prednisolone]]
Line 139: Line 87:
===Antibody-based treatments===
===Antibody-based treatments===


Antibody specific to select immune components can be added to immunosuppressive therapy. The [[monoclonal antibody|monoclonal]] anti-T cell antibody [[OKT3]], once used to prevent rejection, and still occasionally used to treat severe acute rejection, has fallen into disfavor, as it commonly brings severe [[cytokine release syndrome]] and late [[post-transplant lymphoproliferative disorder]]. (OKT3 is available in the [[United Kingdom]] for named-patient use only.)
Antibody specific to select immune components can be added to immunosuppressive therapy. The [[monoclonal antibody|monoclonal]] anti-T cell antibody [[OKT3]], once used to prevent rejection, and still occasionally used to treat severe acute rejection, has fallen into disfavor, as it commonly brings severe [[cytokine release syndrome]] and late [[post-transplant lymphoproliferative disorder]]. (OKT3 is available in the [[United Kingdom]] for named-patient use only.)


'''Antibody drugs''':
'''Antibody drugs''':

* Monoclonal anti-IL-2Rα receptor antibodies
* Monoclonal anti-IL-2Rα receptor antibodies
** [[Basiliximab]]
** [[Basiliximab]]
** [[Daclizumab]]
** [[Daclizumab]]
* Monoclonal anti-IL-6R receptor antibodies
** [[Tocilizumab]]
* Polyclonal anti-T-cell antibodies
* Polyclonal anti-T-cell antibodies
** [[Anti-thymocyte globulin]] (ATG)
** [[Anti-thymocyte globulin]] (ATG)
** [[Anti-lymphocyte globulin]] (ALG)
** [[Anti-lymphocyte globulin]] (ALG)
*Monoclonal anti-CD20 antibodies
* Monoclonal anti-CD20 antibodies
**[[Rituximab]]
** [[Rituximab]]


===Blood transfer===
===Blood transfer===


Cases refractory to immunosuppressive or antibody therapy are sometimes given blood transfusions—removing antibody molecules specific to the transplanted tissue.
Cases refractory to immunosuppressive or antibody therapy are sometimes treated with photopheresis, or extracorporeal photoimmune therapy (ECP), to remove antibody molecules specific to the transplanted tissue.


===Marrow transplant===
===Marrow transplant===


[[Bone marrow transplant]] can replace the transplant recipient's immune system with the donor's, and the recipient accepts the new organ without rejection. The marrow's [[hematopoietic stem cells]]—the reservoir of [[stem cells]] replenishing exhausted blood cells including [[white blood cells]] forming the immune system—must be of the individual who donated the organ or of an [[identical twin]] or a [[cloning|clone]]. There is a risk of [[graft-versus-host disease]] (GVHD), however, whereby mature [[lymphocytes]] entering with marrow recognize the new host tissues as foreign and destroy them.
[[Bone marrow transplant]] can replace the transplant recipient's immune system with the donor's, and the recipient accepts the new organ without rejection. The marrow's [[hematopoietic stem cells]]—the reservoir of [[stem cells]] replenishing exhausted blood cells including [[white blood cells]] forming the immune system—must be of the individual who donated the organ or of an [[identical twin]] or a [[cloning|clone]]. There is a risk of [[graft-versus-host disease]] (GVHD), however, whereby mature [[lymphocytes]] entering with marrow recognize the new host tissues as foreign and destroy them.


==References==
===Gene therapy===
[[Gene therapy]] is another method that can be used. In this method, the genes that cause the body to reject transplants would be deactivated. Research is still being conducted, and no gene therapies are being used to date to treat patients.<ref>{{cite journal | vauthors = Yang JY, Sarwal MM | title = Transplant genetics and genomics | journal = Nature Reviews. Genetics | volume = 18 | issue = 5 | pages = 309–326 | date = May 2017 | pmid = 28286337 | doi = 10.1038/nrg.2017.12 | s2cid = 2222755 }}</ref><ref>{{cite journal | vauthors = Bagley J, Iacomini J | title = Gene therapy progress and prospects: gene therapy in organ transplantation | journal = Gene Therapy | volume = 10 | issue = 8 | pages = 605–611 | date = April 2003 | pmid = 12692588 | doi = 10.1038/sj.gt.3302020 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Giannoukakis N, Thomson A, Robbins P | title = Gene therapy in transplantation | journal = Gene Therapy | volume = 6 | issue = 9 | pages = 1499–1511 | date = September 1999 | pmid = 10490759 | doi = 10.1038/sj.gt.3300981 | doi-access = free }}</ref> Current research tends to focus{{fact|date=January 2022}} on Th1 and Th17 which mediate allograft rejection via the [[Cyclophosphamide#Mechanism of action|CD4]] and CD8 [[T-cell receptor|T cells]].<ref>{{cite journal | vauthors = Yuan X, Paez-Cortez J, Schmitt-Knosalla I, D'Addio F, Mfarrej B, Donnarumma M, Habicht A, Clarkson MR, Iacomini J, Glimcher LH, Sayegh MH, Ansari MJ | display-authors = 6 | title = A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy | journal = The Journal of Experimental Medicine | volume = 205 | issue = 13 | pages = 3133–3144 | date = December 2008 | pmid = 19047438 | pmc = 2605226 | doi = 10.1084/jem.20081937 }}</ref>
{{Reflist|30em}}

== See also ==
* [[Graft-versus-host disease]]
* [[Graft-versus-tumor effect]]
* [[Immunosuppression]]
* [[Transplant engineering]]

== References ==
{{Reflist}}

== External links ==
{{Medical resources
| DiseasesDB =
| ICD10 = {{ICD10|T|86||t|80}}
| ICD9 =
| MedlinePlus = 000815
| eMedicineSubj =
| eMedicineTopic =
| eMedicine_mult =
| MeshID = D006084
}}


==External links==
*[http://www.immunetolerance.org The Immune Tolerance Network]
* [http://www.nlm.nih.gov/medlineplus/ency/article/000815.htm Transplant rejection] // Medline Plus Encyclopedia, 6/14/2011
{{Organ transplantation}}
{{Hypersensitivity and autoimmune diseases}}
{{Hypersensitivity and autoimmune diseases}}
{{Organ transplantation}}


{{DEFAULTSORT:Transplant Rejection}}
{{DEFAULTSORT:Transplant Rejection}}

Latest revision as of 16:03, 9 December 2024

"Host-versus-graft disease" redirects here. For the condition in which transplanted cells attack the recipient's cells, see Graft-versus-host disease.
Transplant rejection
Micrograph showing lung transplant rejection. Lung biopsy. H&E stain.
SpecialtyImmunology
TreatmentImmunosuppressive drugs

Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant.[1]

Types

[edit]

Transplant rejection can be classified into three types: hyperacute, acute, and chronic.[2] These types are differentiated by how quickly the recipient's immune system is activated and the specific aspect or aspects of immunity involved.[3]

Hyperacute rejection

[edit]

Hyperacute rejection is a form of rejection that manifests itself in the minutes to hours following transplantation.[4] It is caused by the presence of pre-existing antibodies in the recipient that recognize antigens in the donor organ.[5] These antigens are located on the endothelial lining of blood vessels within the transplanted organ and, once antibodies bind, will lead to the rapid activation of the complement system.[6] Irreversible damage via thrombosis and subsequent graft necrosis is to be expected.[7] Tissue left implanted will fail to work and could lead to high fever and malaise as the immune system acts against foreign tissue.[8]

Main article: ABO-incompatible transplantation

Graft failure secondary to hyperacute rejection has significantly decreased in incidence as a result of improved pre-transplant screening for antibodies to donor tissues.[4] While these preformed antibodies may result from prior transplants, prior blood transfusions, or pregnancy, hyperacute rejection is most commonly from antibodies to ABO blood group antigens.[6] Consequently, transplants between individuals with differing ABO blood types is generally avoided though may be pursued in very young children (generally under 12 months, but often as old as 24 months)[9] who do not have fully developed immune systems.[10] Shortages of organs and the morbidity and mortality associated with being on transplant waitlists has also increased interest in ABO-incompatible transplantation in older children and adults.[11]

Acute rejection

[edit]
Main article: Histocompatibility

Acute rejection is a category of rejection that occurs on the timescale of weeks to months, with most episodes occurring within the first 3 months to 1 year after transplantation.[6][8] Unlike hyperacute rejection, acute rejection is thought to arise from two distinct immunological mechanisms as lymphocytes, a subset of white blood cells, begin to recognize antigens on transplanted organ/graft.[12] This recognition occurs due to the major histocompatibility complex (MHC), which are proteins on cell surface that are presented to the T-cell receptor found on T-cells.[13] In humans, this is known as the human leukocyte antigen (HLA) system[13] and over 17,000 HLA alleles or genetic variants have been described such that it is extremely uncommon for any two people to have identical alleles.[14] Other non-HLA proteins, known as minor histocompatibility antigens, do exist but generally are unable to cause acute rejection in and of themselves unless a multitude of non-HLA proteins are mismatched.[15] As such, HLA matching (in addition to matching ABO groups) is critical in preventing acute rejection.[16]

This process of recognition by T-cells can happen directly or indirectly and lead to acute cellular and acute humoral rejection respectively.[6] Direct allorecognition is a phenomenon within transplant immunology where the dendritic cells, which are the body's antigen-presenting cells (APCs), migrate from donor tissue to lymphoid tissue (lymphoid follicles and lymph nodes) in the recipient and present their MHC peptides to recipient lymphocytes.[17] In comparison, indirect allorecognition is more analogous to how foreign antigens are recognized by the immune system.[18] Dendritic cells of the recipient come across peptides from donor tissue whether in circulation, lymphoid tissue, or in donor tissue itself.[18] Since not the result of direct antigen presentation, these may not necessarily be intact MHC molecules but instead other proteins that are deemed different enough from recipient may engender a response.[18] This process leads to the priming of T-cells to respond to the peptides secondarily going forward.[2] A third semi-direct pathway has been described in which recipient APCs present fully intact donor MHCs,[17] yet its relative contribution to acute rejection is not as well understood.[15]

Acute cellular rejection occurs following direct allorecognition of mismatched donor MHC by cytotoxic T-cells that begin to secrete cytokines to recruit more lymphocytes as well as cause apoptosis or cell death directly.[4][6] The greater the difference in MHC between donor and recipient, the more cytotoxic T-cells are recruited to damage the graft,[6] which may be seen via biopsy in solid organ transplants, with increased lymphocyte infiltration indicative of more severe acute cellular rejection.[15] Acute humoral rejection is a process usually initiated by indirect allorecognition arising from recipient helper T-cells.[6] These helper T-cells have a crucial role in the development of B-cells that can create donor-specific antibodies.[4] The antibodies deposit themselves within the donor graft and lead to activation of the complement cascade alongside antibody-mediated cytotoxicity with neutrophils, a type of white blood cell separate from lymphocytes, predominantly infiltrating into tissues.[6]

Barring genetically identical twins, acute rejection is to be expected to some degree.[16] Rates of clinically significant acute rejection that could endanger transplant have decreased significantly with the development of immunosuppressive regimens. Using kidney transplants as an example, rates of acute rejection have declined from >50% in the 1970s to 10-20%.[19] Singular episodes of acute rejection, when promptly treated, should not compromise transplant; however, repeated episodes may lead to chronic rejection.[16]

Chronic rejection

[edit]
Micrograph showing a glomerulus with changes characteristic of a transplant glomerulopathy. Transplant glomerulopathy is considered a form of chronic antibody-mediated rejection. PAS stain.

Chronic rejection is an insidious form of rejection that leads to graft destruction over the course of months, but most often years after tissue transplantation.[12] The mechanism for chronic rejection is yet to be fully understood, but it is known that prior acute rejection episodes are the main clinical predictor for the development of chronic rejection.[6] In particular, the incidence increases following severe or persistent acute rejection, whereas acute rejection episodes with return to function back to baseline do not have major effects on graft survival.[20][21] Chronic rejection is generally thought of as being related to either vascular damage or parenchymal damage with subsequent fibrosis.[22] While it is unknown the exact contribution of the immune system in these processes, the indirect pathway of allorecognition and the associated antibody formation seems to be especially involved.[6]

Chronic rejection has widely varied effects on different organs. At 5 years post-transplant, 80% of lung transplants, 60% of heart transplants and 50% of kidney transplants are affected, while liver transplants are only affected 10% of the time.[20] Therefore, chronic rejection explains long-term morbidity in most lung-transplant recipients,[23][24] the median survival roughly 4.7 years, about half the span versus other major organ transplants.[25] Airflow obstruction not ascribable to other cause is labeled bronchiolitis obliterans syndrome (BOS), confirmed by a persistent drop—three or more weeks—in forced expiratory volume (FEV1) by at least 20%.[26] First noted is infiltration by lymphocytes, followed by epithelial cell injury, then inflammatory lesions and recruitment of fibroblasts and myofibroblasts, which proliferate and secrete proteins forming scar tissue.[27] A similar phenomenon can be seen with liver transplant wherein fibrosis leads to jaundice secondary to the destruction of bile ducts within the liver, also known as vanishing bile duct syndrome.[28]

Rejection due to non-adherence

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One principal reason for transplant rejection is non-adherence to prescribed immunosuppressant regimens. This is particularly the case with adolescent recipients,[29] with non-adherence rates near 50% in some instances.[29]

A pilot study conducted by Michael O. Killian PhD from Florida State University and Dr. Dipankar Gupta from University of Florida published in April 2022 in Pediatric Transplantation [30] studied the acceptability and feasibility of an asynchronous directly observed therapy mobile health application among adolescent heart transplant recipients. Patients in the study utilized emocha Health's digital medication adherence program which included asynchronous video messages and chat messages exchanged with a care team. Patients completing the study achieved a 90.1% adherence rate. The researchers noted that further randomized trials are required to confirm the initial findings. However, the results were very promising considering few options exist to support pediatric patients in taking their medications.[citation needed]

Rejection detection

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Diagnosis of acute rejection relies on clinical data—patient signs and symptoms but also calls on laboratory data such as blood or even tissue biopsy. The laboratory pathologist generally seeks three main histological signs: (1) infiltrating T cells, perhaps accompanied by infiltrating eosinophils, plasma cells, and neutrophils, particularly in telltale ratios, (2) structural compromise of tissue anatomy, varying by tissue type transplanted, and (3) injury to blood vessels. Tissue biopsy is restricted, however, by sampling limitations and risks/complications of the invasive procedure.[31][32][33] Cellular magnetic resonance imaging (MRI) of immune cells radiolabeled in vivo might—similarly to Gene Expression Profiling (GEP)—offer noninvasive testing.[34][35]

Rejection treatment

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Hyperacute rejection manifests severely and within minutes, and so treatment is immediate: removal of the tissue. Acute rejection is treated with one or several of a few strategies. Despite treatment, rejection remains a major cause of transplant failure.[36] Chronic rejection is generally considered irreversible and poorly amenable to treatment—only retransplant generally indicated if feasible—though inhaled ciclosporin is being investigated to delay or prevent chronic rejection of lung transplants.

Immunosuppressive therapy

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A short course of high-dose corticosteroids can be applied, and repeated. Triple therapy adds a calcineurin inhibitor and an anti-proliferative agent. Where calcineurin inhibitors or steroids are contraindicated, mTOR inhibitors are used.

Immunosuppressive drugs:

Antibody-based treatments

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Antibody specific to select immune components can be added to immunosuppressive therapy. The monoclonal anti-T cell antibody OKT3, once used to prevent rejection, and still occasionally used to treat severe acute rejection, has fallen into disfavor, as it commonly brings severe cytokine release syndrome and late post-transplant lymphoproliferative disorder. (OKT3 is available in the United Kingdom for named-patient use only.)

Antibody drugs:

Blood transfer

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Cases refractory to immunosuppressive or antibody therapy are sometimes treated with photopheresis, or extracorporeal photoimmune therapy (ECP), to remove antibody molecules specific to the transplanted tissue.

Marrow transplant

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Bone marrow transplant can replace the transplant recipient's immune system with the donor's, and the recipient accepts the new organ without rejection. The marrow's hematopoietic stem cells—the reservoir of stem cells replenishing exhausted blood cells including white blood cells forming the immune system—must be of the individual who donated the organ or of an identical twin or a clone. There is a risk of graft-versus-host disease (GVHD), however, whereby mature lymphocytes entering with marrow recognize the new host tissues as foreign and destroy them.

Gene therapy

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Gene therapy is another method that can be used. In this method, the genes that cause the body to reject transplants would be deactivated. Research is still being conducted, and no gene therapies are being used to date to treat patients.[37][38][39] Current research tends to focus[citation needed] on Th1 and Th17 which mediate allograft rejection via the CD4 and CD8 T cells.[40]

See also

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References

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  1. ^ Frohn C, Fricke L, Puchta JC, Kirchner H (February 2001). "The effect of HLA-C matching on acute renal transplant rejection". Nephrology, Dialysis, Transplantation. 16 (2): 355–360. doi:10.1093/ndt/16.2.355. PMID 11158412.
  2. ^ a b Moreau A, Varey E, Anegon I, Cuturi MC (November 2013). "Effector mechanisms of rejection". Cold Spring Harbor Perspectives in Medicine. 3 (11): a015461. doi:10.1101/cshperspect.a015461. PMC 3808773. PMID 24186491.
  3. ^ Moreau A, Varey E, Anegon I, Cuturi MC (November 2013). "Effector mechanisms of rejection". Cold Spring Harbor Perspectives in Medicine. 3 (11): a015461. doi:10.1101/cshperspect.a015461. PMC 3808773. PMID 24186491.
  4. ^ a b c d Chang YC (2021-01-01). "The surgical and immunosuppressive basis for infections in the pediatric solid organ transplant recipient". In Steinbach WJ, Green MD, Michaels MG, Danziger-Isakov LA (eds.). Pediatric Transplant and Oncology Infectious Diseases. Philadelphia: Elsevier. pp. 1–9.e3. doi:10.1016/B978-0-323-64198-2.00010-5. ISBN 978-0-323-64198-2. S2CID 228907807.
  5. ^ Harmon WE (2010-01-01). "Chapter 41 - Pediatric Renal Transplantation". In Himmelfarb J, Sayegh MH (eds.). Chronic Kidney Disease, Dialysis, and Transplantation (Third ed.). Philadelphia: W.B. Saunders. pp. 591–608. doi:10.1016/B978-1-4377-0987-2.00041-8. ISBN 978-1-4377-0987-2.
  6. ^ a b c d e f g h i j Mak TW, Saunders ME, Jett BD, eds. (2014-01-01). "Chapter 17 - Transplantation". Primer to the Immune Response (Second ed.). Boston: Academic Cell. pp. 457–486. doi:10.1016/B978-0-12-385245-8.00017-0. ISBN 978-0-12-385245-8.
  7. ^ Dharnidharka VR (2019-01-01). "43 - Pediatric Renal Transplantation". In Himmelfarb J, Ikizler TA (eds.). Chronic Kidney Disease, Dialysis, and Transplantation (Fourth ed.). Philadelphia: Elsevier. pp. 661–675.e7. doi:10.1016/B978-0-323-52978-5.00043-4. ISBN 978-0-323-52978-5. S2CID 81475473.
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