Editing Transplant rejection (section)

===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" />