Transplantation Rejection - Clinical Perspective

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Chapter: Pharmaceutical Microbiology : Immunology

This section is intended to provide a brief overview of some clinical issues that exemplify the basic aspects of immune system functioning discussed previously.


SOME CLINICAL PERSPECTIVES OF IMMUNE SYSTEM

 

This section is intended to provide a brief overview of some clinical issues that exemplify the basic aspects of immune system functioning discussed previously.

 

Transplantation Rejection

 

Transplantation is the process of transferring cells, tissues or organs—termed a graft—from one location to another. An autologous graft is a transplant between two sites within the same individual, e.g. skin graft from the thigh to the hand. An allogeneic graft is a transplant between two genetically different individuals of the same species,

e.g. kidney transplant from a donor to a recipient individual. A xenogenic graft is a transplant across different species, e.g. pig to human.

The tempo of clinical rejection—in kidney transplantation, for example—is often categorized by the following stages.

•        Hyperacute rejection occurs within minutes to hours following revascularization of a graft. The cause is due to the presence of preformed circulating antibody (IgG) that reacts with the blood cell antigens (the ABO system), or MHC I molecules or other poorly defined antigens. This should now be a rare event clinically as recipients are tested (cross-matched) before transplantation for the presence of antibodies reactive with cells of the donor.

•        Acute rejection occurs within weeks to months following transplantation and involves humoral (antibody) and cell-mediated induced cytotoxicity. Damage may be reversed with early diagnosis and more aggressive immunosuppressive therapy.

•        Chronic rejection occurs many months or even years following transplantation. The pathology is characterized by fibrosis and may require differential diagnosis to distinguish between a chronic rejection event and the recurrence of the original disease that necessitated transplantation in the first place.

The major alloantigens (i.e. antigens responsible for rejection of allogeneic grafts) are the MHC proteins. Although there are two distinct classes of MHC protein (described in section 4.1), the MHC molecules actually have a number of subclasses which vary further in the general nature of peptides that they will accept within their binding clefts. The MHC I molecules are composed of three subclasses, MHC IA, MHC IB and MHC IC, on each nucleated cell of the body; all three subclasses are simultaneously expressed. The MHC II molecules are also made up of three subclasses, MHC II DR, MHC II DP and MHC II DQ, and again on each APC all three subclasses of MHC II molecule are simultaneously expressed. APCs, like other cells in the body, will also express MHC I molecules on their surface in addition to MHC II.

As indicated previously, the major cause of allogeneic tissue transplantation rejection is the polymorphic nature of the MHC phenotype between individuals. Polymorphism in MHC arises within the population because the genes for each of the MHC subclasses can exist in multiple different forms or alleles. For example, in humans there are at least 52 different forms of the MHC IB gene and at least 24 different forms of the MHC IA gene. It follows that individuals in a population can possess any one of the 52 different forms of MHC IB gene and any one of the 24 different forms of MHC IA gene, so the number of different combinations for the six classes of MHC proteins is many millions. The situation is further complicated by the fact that each individual inherits and co-expresses a set of MHC I and II genes from each parent. This means that on each nucleated cell of the body there will be co-expressed paternally derived and maternally derived versions of the MHC IA, MHC IB and MHC IC molecules. The same principle will apply for co-expression on APCs of paternal and maternal MHC II protein subclasses.

This tremendous polymorphism is important in immune defence because it allows the broadest possible scope of peptide antigen presentation, and thus the best chance of survival of a population as a whole, but it also confers the very high probability of MHC mismatch during allogeneic transplantation. As a result of the mode of MHC inheritance, the highest probability of a MHC tissue match between individuals who are not genetically identical twins will be that obtained between siblings, where there is a 1 in 4 chance of a sibling possessing an exact match for all the MHC I and MHC II subclasses. The MHC proteins are also termed human leucocyte antigens (HLA), and HLA tissue typing is undertaken routinely before transplantation to gain improved matches between donor and recipient. In kidney transplantation it has been found that matching the MHC IA, IB and IIDR genes in particular appears to improve shortand long-term graft survival.

The main target for the modern immunosuppressants such as ciclosporin and tacrolimus is inhibition of cytokine gene transcription in a highly selective manner in the helper T-lymphocyte populations. The consequence of this is to inhibit helper T-cell autoactivation and helper T-cell coactivation of cytotoxic T-lymphocytes and of B-lymphocytes, and thus considerably ‘damp down’ cell-mediated and humoral immune responses to the graft.

 

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