III. Cellular Xenograft Rejection (ACXR)
Here there is T cell rejection which occurs. T cells can recognize antigens on donor APCs or as peptides on MHC molecules. Both cases there are high xenoreactive precursor's frequency seen.
CDR1/CDR2 interaction with non self MHC may be a cause for xenograft rejection. It was however seen that peptide specific for human anti-pig CTL after many stimulations show CDR3 is also involved. In cellular xenografts the indirect pathway is dominant. This can be seen invivo by response to porcine cells; here macrophages initiate a response by presenting xeno antigens to Th cells which lead to rejection. Elimination of CD4+ T cell is not enough for inhibiting pig rejection. Absence of MHC II expressed on donor cells may be the indirect pathway. Vascular thrombosis and interstitial hamerroage are absent in ACXR however infiltrates are seen. Mononuclear cells, including T cells, B cells and in some cases NK cells and macrophages are present in infiltrates which can be seen in ACXR. The T cell response has been studied both invivo and invitro.

Ways to overcome ACXR:
Thymic transplantation approach was the first shown to induce robust xenograft tolerance. The pig thymus replaced the host thymus permitting peripheral T cell reconstitution and donor specific xenograft tolerance was achieved. Murine T cells cleared opportunistic infections. Tolerisation of human T cells to pig. Porcine thymus grafts were shown to support human T cell development from stem cells.

Mixed chimerism was done to induce tolerance in mice before transplantation in human is possible. Mixed chimerism refers to the coexistence of donor and recipient haemopoeitic cells with donor representation that can be detected by non PCR based techniques. Mixed chimerism is also called macrochimerism. Mixed chimerism maintains robust tolerance through well defined and clinically desirable mechanism of intrathymic clonal deletion of donor reactive cells. The possibility to inactivate and eliminate only donor specific T cells while leaving the remaining TCR essentially intact is by using a mechanism that involves peripheral clonal deletion after BMT with co stimulatory blocking agents.

Microbial problems are also a cause for xeno graft rejection. There is a need to decrease the risk of potential transmission of infectious agents through this approach. Studies assessing the safety of xenotransplantation are ongoing and are focused on viruses especially PERV which is encoded in germ line DNA. There are three classes of infectious viruses which are identified (PERV-A, PERV-B & PERV-C). These are classified based on difference in receptor recognition. PERV-A & PERV-B can infect human cells invitro, PERV-C lack this. In vivo recombination between PERV-A & PERV-C is possible and can produce a human tropic recombinant virus. No infection with any PERV seen even if recombination of PERV-A/C virus has been reported. The exogenous viruses are herpes viruses in pigs like PCMV (porcine cytomegalovirus) & porcine lymphotropic virus 1, 2 & 3. Although PCMV activation has been documented in pig-to-primate xenografts, causing clinical disease in the xenotransplanted organ and the detection of viral DNA in primate tissues; it does not appear to cause invasive disease in transplanted primates. Moreover, it has been demonstrated that PCMV can be effectively excluded from source pigs by early weaning.

Ways to reduce the microbial risks:
ï'˜ Use of immunosuppressive regimes and tolerance induction protocols minimize xenograft rejection caused by microbes.
ï'˜ Viruses released by cells that do not express αGal, such as those of αGalT−/− pigs, lack αGal epitopes on their envelope and cannot be recognized by anti αGal antibodies, therefore becoming less sensitive to complement-mediated inactivation.
ï'˜ Presence of human complement regulators on transgenic pig cells may reduce complement- mediated defense mechanisms against infections. Hence genetically engineered pig lines expressing such human complement regulatory proteins, pig viruses may adapt to infect humans once porcine organs have been transplanted.
ï'˜ Genetic manipulation of the porcine genome may provide an additional strategy to remove the viral risk.
ï'˜ Finally careful monitoring of the organs which need to be transplanted also helps to reduce this problem.

Ethical problems are many in number and have been highlighted as the major subjects in the debate related to xenotransplantation.

ï'˜ Strict requirements for patients informed consent.
ï'˜ Potential risks of infections and epidemics by transmission of xenogenic pathogens.
ï'˜ Social acceptance of xenografts.

Pathophysiological problems associated with xenotransplantation are molecular differences between complement and coagulation systems of pig and primate. Anemia is also observed in pig to primate transplantation. The pig body temperature is normally approximately 103ºF and the metabolism of pig cells may be less than optimal at the human body temperature of 98.6ºF.

However, even with all these drawbacks the pig seems to be the most ideal animal for xenotransplantation. The organ shortage is overcome by using pigs as donors for humans; however more study and clinical trials need to be done in order to make it more practical and risk free. To conclude xenotransplantation is a boon to the human society if used wisely.

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