TRANSPLANTATION REJECTION

1.         Role of Immune system in Transplantation

a.         The transplantation of tissues to replace disease organs is now an important medical therapy.

b.         In most cases, adaptive immune responses to the grafted tissues are the major impediment to successful transplantation.

c.         When tissues containing nucleated cells are transplanted, T-cell responses to the highly polymorphic MHC molecules almost always trigger a response against the grafted organ.

d.            Matching the MHC type of donor and recipient when increases the success rate of grafts, but perfect matching is possible only when donor and recipient are related and, in these cases, genetic differences at other loci still trigger rejection.

e.         An autograft (transfer of an individual’s own tissue) and syngeneic graft (a transfer of tissue between genetically identical individuals) are always accepted.

f.          An allograft is a graft between genetically different members of the same species.

2.            Allograft rejection

a.         Unless immunosuppressive measures are taken, allografts are rejected by a processed called the allograft reaction.

b.         First-set rejection:

i.          in an acute allograft reaction, vascularization of the graft is normal initially, but in 11-14 days, marked reduction in circulation and mononuclear cell infiltration occurs, with eventual necrosis.

ii.          a T cell-mediated reaction is the main cause of rejection of many types of grafts.

c.            Second-set rejection:

i.          if a second allograft from the same donor is applied to a sensitized recipient, it is rejected in 5-6 days.

ii.          this accelerated reaction is caused primarily by presensitized cytotoxic T cells.

d.            Hyperacute graft rejection:

i.            antibody responses are also an important potential cause of graft rejection.

ii.            alloantibodies to blood group antigens and polymorphic MHC antigens can cause rapid rejection of transplanted organs in a complement-dependent reaction.

iii.         most grafts that are transplanted routinely are vascularized organ grafts linked directly to the recipient’s circulation.

iv.         in some cases, the recipient may already have circulating antibodies to donor graft antigens, which were produced in response to a previous transplant or a blood transfusion.

v.         such antibodies can cause very rapid rejection of vascularized grafts, since they react with antigens on the vascular endothelial cells of the graft and initiate the complement and clotting cascades.

3.            Matching Donor and Recipient

a.            Importance of MHC proteins:

i.          the acceptance or rejection of a transplant is determined, in large part, by the class I and class II MHC proteins on the donor cells, with class II playing the major role.

ii.          the proteins encoded by the DR locus are especially important.

iii.         these alloantigens activate T cells, both helper and cytotoxic, which bear T cell receptors specific for the alloantigens.

iv.         the activated T cells proliferate and then react against the alloantigens on the donor cells.

v.         CD8-positive cytotoxic T cells do most of the killing of the allograft cells.

b.         Finding a correct MHC match:

i.          prior to transplantation surgery, laboratory tests are performed to determine the closet match of MHC proteins in the donor and recipient.

ii.          class I proteins and certain class II proteins, especially DR, are detected by using a panel of known antibodies plus complement to lyse donor lymphocytes.

iii.            additional information regarding the compatibility of the class II proteins is determined by the mixed leukocyte reaction with cultured cells.

c.            Limitations:

i.          HLA typing is imprecise, owing to the polymorphism and complexity of the human MHC; unrelated individuals who type as HLA-identical using antibodies to MHC proteins rarely have identical MHC genotypes.

ii.            however, this should not be a problem with HLA-identical siblings because siblings inherit their MHC genes ass a haplotype, one sibling in four should be truly HLA-identical.

iii.            nevertheless, grafts between HLA-identical siblings are invariably rejected, albeit more slowly unless they are identical twins as a result of minor histocompatibility antigens.

d.         Minor H antigens:

i.          they are peptides derived from polymorphic proteins that are presented by MHC molecules on the graft.

ii.          as all cells in the graft express the minor H antigen, the entire graft is destroyed eventually.

e.         Among a siblings in a single family, there is a:

i.          25% chance for both haplotypes to be shared.

ii.          50% chance of one haplotype to be shared.

iii.         25% chance of no haplotypes to be shared.

f.            Crossmatching:

i.          cross-matching, as in blood transfusion, involves determining whether the recipient has antibodies that react with the white blood cells of the donor.

ii.            preformed cytotoxic antibodies in the recipient’s serum reacted against the graft are detected by observing the lysis of donor lymphocytes by the recipient’s serum plus complement.

iii.         the donor and recipient are also matched for the compatibility of their ABO blood groups.

iv.         this is done to prevent hyperacute rejections from occurring.

4.         Graft-versus-Host Reaction

a.         Well-matched transplants of bone marrows may establish themselves initially in 85% of recipients but subsequently a graft-versus-host (GVH) reaction develops in about two-thirds of them.

b.         This reaction occurs because grafted immunocompetent T cells proliferate in the irradiated, immunocompromised host and ‘reject’ cells with class II proteins, resulting in severe organ dysfunction.

c.            Symptoms of GVH reaction:

i.            maculopapular rash, jaundice, hepatosplenomegaly, and diarrhea.

ii.          many GVH reactions end in overwhelming infections and death.

d.            Requirements for occurrence of GVH reaction:

i.          the graft must contain immunocompetent T cells.

ii.          the host must be immunocompromised.

iii.         the recipient must express antigens foreign to the donor.

e.         The GVH reaction can be reduced by treating the donor tissue with antithymocyte globulin or monoclonal antibodies before grafting; this eliminates mature T cells from the graft.

5.         Use of Immunosuppressants in Transplants

a.            Immunosuppressants are used to reduce the chance of rejection of transplanted tissue.

b.            Cyclosporin A:

i.            prevents the activation of T lymphocytes by inhibiting signal transduction within T cells.

ii.            interrupts signal transduction by inhibiting calcineurin, a protein involved in the activation of the genes for IL-2 and the IL-2 receptor.

iii.         it is well-tolerated and is remarkably successful in preventing the rejection of transplants.

c.            Tacrolimus is more immunosuppressive but causes more side effects.

d.            Corticosteroids act primarily by inhibiting cytokine production by macrophages and by lysing certain types of T cells.

e.            Azathioprine is an inhibitor of DNA synthesis and blocks the growth of T cells.

f.          OKT3 is a monoclonal antibody against the CD3 protein that can block T cell function as well as lyse T cells.

g.         Side effects:

i.            immunosuppression greatly enhances the patient’s susceptibility to opportunistic infections and neoplasms.

ii.          the incidence of cancer is as much as 100-fold increased in transplant recipients.