Editing Transplant rejection (section)

==Types==
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===

'''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>

{{main|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.<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>

===Acute rejection===

{{Main|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.<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 [[Protein|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>

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" />

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" />

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===
[[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" />

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>