علن المناعة

اغتراس الاعضاء ورفض

الغرسات/الطعوم

Transplantation and Rejection of Transplants

الخانيرائدة . د.أ

10محاضرة

أنواع الاغتراس

Rejection of Transplants

Rejection is a process in which T lymphocytes and antibodies produced against graft antigens react against and destroy the grafts as the recipient’s immune system recognizes the graft as foreign and attacks it.

HLA genes are highly polymorphic; that is, there are alternative forms (alleles) of each gene at each locus estimated to number over 10,000 for all HLA genes and over 3500 for HLA-B alleles alone.

Even grafts from a donor to a sibling with the same HLA haplotype may be rejected because of differences in so-called “minor histocompatibility loci”, other sets of polymorphic genes that are likely to differ by chance.

The key to successful transplantation has been the development of therapies that prevent or minimize rejection

• The recipient’s T cells recognize donor antigens from the graft (the allogeneic antigens, or alloantigens) and activated by two pathways:

1- Direct Pathway: The graft antigens are presented directly to recipient T cells by graft APCs

2- Indirect Pathway: The graft antigens are picked up by host APCs, processed (like any other foreign antigen), and presented to host T cells.

• Both pathways lead to activation of CD8 and CD4 cells. Indirect path. Activate B cells

• Immune responses to allografts are stronger than responses to pathogens

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Mechanisms of Graft Rejection

Graft rejection is classified into

hyperacute, acute, and chronic,

on the basis of clinical and pathologic features.

1- Hyperacute rejection:

• Mediated by preformed antibodies specific for

antigens on graft endothelial cells, IgM antibodies

specific for blood group antigens, or antibodies

specific for allogeneic MHC molecules induced by

prior exposure through blood transfusions,

pregnancy, or organ transplantation.

• Antibodies bind to antigens on the graft endothelium

and activate the complement and clotting systems,

leading to endothelial injury, thrombus formation,

and ischemic necrosis of the graft.

Hyperacute rejection is not a common problem, because every donor and recipient are matched for blood type and potential recipients are tested for antibodies against the cells of the prospective donor, a test called a cross-match.

o The affected kidney rapidly becomes cyanotic and mottled

o Necrosis of the wall of capillaries, arterioles and arteries with occlusion of their lumens by thrombi.

o Neutrophils rapidly accumulate within arterioles, and glomeruli.

o Necrosis of the kidney cortex undergoes necrosis o Affected kidneys are nonfunctional and have to

be removed.

2-Acute rejection • Mediated by T cells and antibodies

1. Acute cellular rejection: activated by alloantigens in the graft.

• Occurs within days or weeks after transplantation, although it may appear suddenly months or even years later, after immunosuppression is terminated

• It is the principal cause of early graft failure.

• CD8+ CTLs may directly destroy graft cells, or CD4+ cells secrete cytokines and induce inflammation, which damages the graft

• Current immunosuppressive therapy is designed mainly to prevent and reduce acute rejection by blocking the activation of alloreactive T cells.

• Acute cellular rejection may produce two different patterns of injury.

- tubulointerstitial pattern: sometimes called type I, there is extensive interstitial inflammation and tubular inflammation (tubulitis) contain activated CD4+ and CD8+ T lymphocytes.

- The vascular pattern shows inflammation of vessels (type II), or sometimes necrosis of vessel walls (type III).

• The recognition of cellular rejection is important because, in the absence of accompanying humoral rejection, most patients respond well to immunosuppressive therapy.

2. Acute antibody-mediated rejection= vascular or humoral rejection

• Antibodies bind to vascular endothelium and activate complement via the classical pathway >> inflammation and endothelial damage >> cause graft failure

• Rejection is manifested mainly by damage to glomeruli and small blood vessels. Typically, there is inflammation of glomeruli and peritubular capillaries associated with deposition of complement products, which is due to activation of the complement system by the antibody-dependent pathway.

• Small vessels also may show focal thrombosis.

3- Chronic rejection • Possibly mediated by T cells and alloantibodies

• T cells react against graft alloantigens and secrete cytokines, which stimulate the proliferation and activities of fibroblasts and vascular smooth muscle cells in the graft.

• Interstitial fibrosis and gradual narrowing of graft blood vessels (graft arteriosclerosis) with duplication of basement membranes in glomeruli

• Indolent form of graft damage that occurs over months or years, leading to progressive loss of graft function

• Refractory to most therapies and is becoming the principal cause of graft failure.

Methods of Increasing Graft Survival

Because HLA molecules are the major targets in transplant rejection, better matching of the donor and the recipient improves graft survival; survival improves with increasing number of loci matched notably for kidney transplant.

As immunosuppression is improved, HLA matching is no longer done for heart, lung, liver, and islet transplantation; in such instances, the recipient often needs a transplant urgently and other considerations, such as anatomic compatibility, are of greater importance.

Immunosuppression of the recipient is a necessity in all organ transplantation, except in the case of identical twins.

Opportunistic Infections

• Suppression of the immune system results in increased susceptibility to opportunistic fungal, viral, and other infections.

• Reactivation of latent viruses, such as cytomegalovirus (CMV), are frequent complications.

• Immunosuppressed patients also are at increased risk for developing virus-induced tumors, such as Epstein-Barr virus (EBV)–induced lymphomas and human papillomavirus (HPV)–induced squamous cell carcinomas.

Induction of donor-specific tolerance in host T cells

• Prevent host T cells from receiving costimulatory signals from donor DCs during the initial phase of sensitization by administration of agents that block the interaction of the B7 molecules on the DCs of the graft and the CD28 receptor on host T cells.

• Injecting into recipients regulatory T cells enriched for cells specific for donor alloantigens

Transplantation of Hematopoietic Stem Cells

• Indicated for hematologic malignancies, bone marrow failure syndromes (such as aplastic anemia), and disorders caused by inherited HSC defects .

• Historically, HSCs were obtained from the bone marrow, but now they usually are obtained from peripheral blood, or from the umbilical cord blood of newborn infants, a rich source of HSCs.

• In most of the conditions in which HSC transplantation is indicated, the recipient is irradiated or treated with chemotherapy to destroy the immune system (and sometimes, cancer cells) and to “open up” niches in the microenvironment of the marrow allowing the transplanted HSCs to engraft.

Graft-Versus-Host Disease

• GVHD occurs when the transferred cells recognize alloantigens in the host and attack host tissues.

• It occurs when immunologically competent cells or their precursors are transplanted into immunologically crippled recipients.

• Most common in the setting of HSC transplantation

• Rarely, may occur following transplantation of solid organs rich in lymphoid cells (e.g., the liver)

• An immunologically compromised host cannot reject the graft, but T cells present in the donor graft perceive the host’s tissue as foreign and react against it >> results in the activation of donor CD4+ and CD8+ T cells, ultimately causing inflammation and killing recipient cells.

• To minimize GVHD, HSC transplants are done between donor and recipient that are carefully HLA-matched

Two forms of GVHD

Acute GVHD:

• Occurring days to weeks after transplantation.

• Causes epithelial cell necrosis in three principal target organs: liver, skin, and gut.

• Clinical presentation: jaundice, mucosal ulceration of the gut results in bloody diarrhea. Cutaneous involvement manifests as a rash

Chronic GVHD:

• may follow the acute syndrome or may occur insidiously.

• Patients develop skin lesions resembling those of autoimmune disorders.