Immunology And Immunogenetics Potential Donor Selection Biology Essay

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In the modern definition of a suitable donor physical condition is a major factor and there is no age limits to donation. Although for living donors the age should be over 18.

The potential donors must be checked for infectious diseases such as HIV, hepatitis C, hepatitis B, acute hepatitis, cytomegalovirus, Epstein-Barr virus, active syphilis, viral infection sepsis, tuberculosis, infection of unknown aetiology, family history of Creutzfeildt-Jacob disease. Any of these infectious diseases make a donor unsuitable for transplant.

Active cancer or history of metastatic cancer leads to refuse the donor.

Vascular conditions and renal function are important factors for selection. Prolonged history of diabetes mellitus or serious hyper-tensions with retinal vascular damage may result in organ failure.

Renal function is evaluated in potential donor. Acute renal failure is not itself a contradiction.

HLA matching is still very important in kidney transplantation. HLA incompatibility can result in proliferation and activation of the recipient's CD4+ and CD8+ T cells with contaminant activation of B cell allo-antibody production. The HLA-A, HLA-B and HLA-DR phenotypes should be determined in all potential recipients and donors. Also for living donors, although HLA compatibility is less important.

ABO incompatibility can cause early hyper acute rejection (HAR). ABO blood group antigens are present on kidney grafts, particularly those from A or B secretors, and preformed naturally occurring antibodies to blood group substances are present in mismatched recipients.

Laboratory Tests:

PCR laboratory- DNA amplification assays for easy detection and quantitification for purpose of disease diagnosis, such as Hepatitis B and C. HLA class I and II typing of donor and recipients.

Complement dependent cytotoxicity (CDC) or enzyme linked immunosorbent assay (ELISA)- screening for HLA specific antibodies in patients serum. CDC could detect the anti-HLA antibodies. ELISA is quantitative binding assay which can detect any class of antibody. ELISA is more sensitive than CDC.

Flow cytometry- It detects all IgG antibodies but not IgM. Flow cytometry is more sensitive then CDC, it is a quantitative binding assay, results are read electronically as fluorescent intensity and it can be used for antibody detection or antibody definition.

ABO typing is another test performed before transplantation.

Crossmatching is a very sensitive and final test performed on a kidney donor and a particular recipient. The basic crossmatch test involves a mixing of cells and serum to determine whether or not the recipient of a kidney will respond to the transplanted organ by attempting to reject it.

Other tests that may be necessary before a patient can be put on the waiting list for a transplant include: an electrocardiogram (ECG), (an electric recording of the heart) an echocardiogram (echo), (a sound-wave picture of the heart) and a chest X-ray.

Kidney Transplantation

Sibling 3 (shares one HLA haplotypes) and Sibling 2 (completely different HLA haplotypes) is a suitable kidney donor for Fred. Although the best donor is Sibling 1 (shares both HLA haplotype. The best compatibility is a six-antigen match between donor and recipient, which occurs in 25% of sibling, also sometimes occurs in population. The best long-term outcomes are between persons who share all antigens. Donors and recipients who match at five antigens may not do quite as well over the long term as the six-antigen matched donor recipient pairs, but will do statistically better than donors and recipients matched at four antigens and so on. According to Cecka J.M. (2001) "Renal grafts from HLA-identical sibling donors have a 10-year survival of about 74%. Those from "6 antigen-matched" cadavers have a survival of 57% (65% if HLA identical by DNA typing) at 10 years. Grafts from family members sharing one haplotype have a 10-year survival of about 54%. Those from HLA mis-matched cadaveric donors have a survival of 40% at 10 years".

In the recent years immunosuppressive drugs improved the long-term outcomes between non-match HLA haplotypes (zero haplotype match) between living donor and recipient.

Bone Marrow Transplantation

Sibling 1 is the only possible bone marrow donor to Fred. A bone marrow transplant will not usually be done unless 5 out of 6 of these antigens match, and 6 out of 6 is considered best.

Matching of additional HLA antigens (beyond HLA-A, HLA-B and HLADR) is optimal and reduces chances of long-term complications. highly HLA-disparate family or more than one mismatch URD should be avoided.

In bone marrow transplantation mismatches at HLA-A, -B, -C, and -DRB1 each had similar adverse effects on mortality. HLA-A mismatches have a highly influence possibility of developing GVHD. Mismatches for HLA-DQ or -DP did not significantly affect outcome.

Difference between bone marrow transplantation from graft of solid organs, such as kidney is that immuno-competent cells from both recipient and the donor marrow has the ability to reject each other, which leads to GVHD or graft rejection.

In the bone marrow transplantation the donor bone marrow cells may recognize the cells as foreign and attack the recipient that can range from mild to fatal. It is known as graft versus host disease (GVHD). Recipients who have received stem cells/bone marrow from an HLA (human leukocyte antigen) mismatched related donor or from an HLA matched unrelated donor have an increased risk of developing acute GVHD.

The second concern is that successful bone marrow grafting usually results after strict donor and recipient MHC class II antigen compatibility to minimize the possibility of graft rejection and GVHD.

In MHC-matched transplants, T-cell receptors (TCRs) recognize miHAs, which are the distinct peptide products of polymorphic genes that distinguish the recipient from the donor. Minor histocompatibility antigens (miHAs) are known targets of donor T cells after allogenic hematopoietic stem cell transplantation (HSCT), leading to graft versus host disease after transplantation. (figure 1)

From: Warren D. Shlomchik, Nature Reviews Immunology 7, 340-352 (May 2007), doi:10.1038/nri2000

Figure 1-a. In the initiation phase, donor CD8+ T cells recognize the peptide products of polymorphic genes (minor histocompatibility antigens) then they are loaded onto MHC class I molecules (class I pathway). The peptide-MHC class I complex is then exported to the cell surface where the peptide is recognized as foreign by donor CD8+ T cells. By contrast, initial CD4+ T-cell activation can be directed towards antigens that are endocytosed by recipient- or donor-derived APCs and processed by the class II pathway. Targeting of only exogenously acquired non-haematopoietic antigens is sufficient for inducing CD4+ T-cell-mediated graft-versus-host disease (GVHD). b .After the initiation phase, donor APCs can activate donor CD8+ T cells by cross-presenting exogenously acquired antigens (through the uptake of apoptotic recipient or shed proteins) on MHC class I molecules. Alternatively or in addition, donor APCs could activate naive donor CD8+T cells against new, non-haematopoietic antigens (epitope spreading).

Ethical Issues - Primary Ethical Principle

A central tenet of medical ethics is obligation to do good and avoiding harm for patients, although no physiological good will occur to a donor, psychological benefits to the living donor justify the risk involved. Make sure that there is appropriate balance between benefit and harm.

A high standard of donor assessments and risk limitation is very important.

The physical and psychological well-being of the donor are the primary issues that have to be considered.

Each donor should have an advocate to provide unbiased advice on the donation process and there should be separated of the recipient and donor teams.

The donor must be given a psychological evaluation by a mental health professional to asses the donor's ability to make his/her decision.

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