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 similaity between donor and recipient and by use of immunosuppressant drugs after transplant.
Transplant rejection is classified into three types: hyperacute, acute, and chronic.
Hyperacute rejection manifests itself in the minutes to hours following transplantation, and is caused by the presence of pre-existing antibodies in the recipient that recognize antigens in the donor organ.
These antigens located on the endothelial lining of blood vessels within the transplanted organ are bound to antibodies leading to the rapid activation of the complement system.
Irreversible damage via thrombosis and subsequent graft necrosis occurs.
Tissue left fail to work and could lead to high fever and malaise as the immune system acts against foreign tissue.
Graft failure secondary to hyperacute rejection has significantly decreased in incidence due tomimproved pre-transplant screening for antibodies to donor tissues.
Preformed antibodies may result from prior transplants, prior blood transfusions, pregnancy, and hyperacute rejection is most commonly from antibodies to ABO blood group antigens.
Transplants between individuals with differing ABO blood types is avoided though may be pursued in very young children who are generally under 12 months, but often as old as 24 months, who do not have fully developed immune systems.
Acute rejection occurs on the timescale of weeks to months, with most episodes occurring within the first 3 months to 1 year after transplantation.
Unlike hyperacute rejection, acute rejection arises from immunological mechanisms as lymphocytes, begin to recognize antigens on transplanted organ/graft.
This recognition of antigens 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.
The human leukocyte antigen (HLA) System has over 17,000 HLA alleles or genetic variants.
It is extremely uncommon for any two people to have identical alleles.
Other non-HLA proteins, known as minor histocompatibility antigens, generally are unable to cause acute rejection in and of themselves unless a multitude of non-HLA proteins are mismatched.
HLA matching And matching ABO groups, is critical in preventing acute rejection.
This process of recognition by T-cells can happen directly or indirectly and lead to acute cellular and acute humoral rejection respectively.
Direct allorecognition in transplant immunology is where the dendritic cells, which are the body’s antigen-presenting cells (APCs), migrate from donor tissue to lymphoid tissue in the recipient and present their MHC peptides to recipient lymphocytes.
Indirect allorecognition is more analogous to how foreign antigens are recognized by the immune system.
Dendritic cells of the recipient come across peptides from donor tissue whether in circulation, lymphoid tissue, or in donor tissue itself.
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.
This process leads to the priming of T-cells to respond to the peptides secondarily going forward.
A third semi-direct pathway has been described in which recipient APCs present fully intact donor MHCs.
Acute cellular rejection occurs following direct allorecognition of mismatched donor MHC by cytotoxic T-cells.
The T-cells begin to secrete cytokines to recruit more lymphocytes as well as cause apoptosis or cell death directly.
The greater the difference in MHC between donor and recipient, the more cytotoxic T-cells are recruited to damage the graft.
Damage may be seen via biopsy in solid organ transplants, with increased lymphocyte infiltration indicative of more severe acute cellular rejection.
Acute humoral rejection is usually initiated by indirect allorecognition arising from recipient helper T-cells.
These helper T-cells have a role in the development of B-cells that can create donor-specific antibodies.
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.
Except in genetically identical twins, acute rejection is to be expected to some degree.
Clinically significant acute rejection that could endanger transplant have decreased significantly with the development of immunosuppressive regimens.
Kidney transplants as an example, rates of acute rejection have declined from >50% in the 1970s to 10-20%.
Singular episodes of acute rejection, when promptly treated, should not compromise transplant; however, repeated episodes may lead to chronic rejection.
Transplant glomerulopathy is considered a form of chronic antibody-mediated rejection.
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.
Prior acute rejection episodes are the main clinical predictor for the development of chronic rejection.
Chronic rejection 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.
Chronic rejection is generally thought of as being related to either vascular damage or parenchymal damage with subsequent fibrosis.
The indirect pathway of allorecognition and the associated antibody formation seems to be especially involved.
Chronic rejection 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.
Chronic rejection explains long-term morbidity in most lung-transplant recipients, the median survival roughly 4.7 years, about half the span versus other major organ transplants.
Airflow obstruction not ascribable, after lung transplant, 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%.
Lung transplant rejection first has 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.
A similar process 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.
A principal reason for transplant rejection is non-adherence to prescribed immunosuppressant regimens.
With adolescent recipients 29% have non-adherence rates, with near 50% in some instances.
The laboratory histological signs of rejection: 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.
Rejection treatment:
A hyperacute rejection manifests severely and within minutes, and so treatment is immediate: removal of the tissue.
Despite treatment, rejection remains a major cause of transplant failure.
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.
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: Corticosteroids Prednisolone Hydrocortisone Calcineurin inhibitors Ciclosporin Tacrolimus
Anti-proliferatives Azathioprine Mycophenolic acid mTOR inhibitors Sirolimus Everolimus
Antibody specific to select immune components can be added to immunosuppressive therapy.
Antibody drugs: Monoclonal anti-IL-2Rα receptor antibodies Basiliximab Daclizumab Monoclonal anti-IL-6R receptor antibodies Tocilizumab Polyclonal anti-T-cell antibodies Anti-thymocyte globulin (ATG) Anti-lymphocyte globulin (ALG) Monoclonal anti-CD20 antibodies Rituximab
In cases refractory to immunosuppressive or antibody therapy are sometimes treated with photopheresis, or extracorporeal photoimmune therapy to remove antibody molecules specific to the transplanted tissue.
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 bone 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) with allogeneic transplant however, whereby mature lymphocytes entering with marrow recognize the new host tissues as foreign and destroy them.