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xenoreactive antibody, the binding of antibody to rejecting porcine xenografts has been a reproducible observation in preclinical primate studies. Xenoreactive antibodies may potentiate, even help initiate the process of endothelial cell activation, and can potentiate the cytotoxic effects of graft infiltrating effector cells. Further examination of the B-cell compartment in xenotransplantation is clearly warranted.

The strength of the immune response to xenografts has encouraged efforts to induce tolerance, with the hope of avoiding the deleterious consequences of excessive recipient immunosuppression. Approaches have included attempts to induce mixed hematopoietic chimerism through the use of donor bone marrow derived cells. More recently, transplantation of fetal pig thymus and liver tissue to thymectomized, irradiated, T- and NK cell depleted mice has been shown to induce long standing donor specific tolerance across a discordant species barrier. Less convincing results for tolerance induction have been achieved in nonhuman primates, where problems related to xenoractive antibodies and potential incompatibility of growth factors have been identified. Modifications, including the use of strategies to absorb pre-existing xenoractive antibodies, B-cell depletion of autologous bone marrow, transfection of autologous bone marrow cells to express xenogeneic MHC antigen, and the use of donor-specific growth factors to promote bone marrow chimerism may prove useful in achieving tolerance in the pig to human species combination. Alternatively, the use of newly developed reagents for blockade of costimulation, such as CTLAIg and CD40 ligand may be sufficient to achieve a state of peripheral T-cell tolerance or anergy without the need for aggressive ablative regimens. It remains to be seen if effective control of the xenogeneic cellular immune responses can be achieved in a safe and clinically applicable manner.

Selected Readings

1. Xenotransplantation; The Transplantation of Organ and Tissues between species 2nd Edition Cooper DKC, Kemp E, Platt JL, White DJG (eds) Springer Verlag 1997.

2. Bach FH, Hancock WW, Ferran C. Protective genes expressed in endothelial cells: A regulatory response to injury. Immunol Today 1997 Oct; 18(10):483-6.

3. Auchincloss H, Sachs DM. Xenogeneric transplantation. Ann Rev Immunol 1998; 16:433-70.

4. Lambights D, Sachs DM, Cooper DK. Discordant organ xenotransplantation in primates: World experience and current status. [Review] Transplantation 1998 Sep; 66(5):547-61.

5. Platt JL, Lin SS, McCregor CG. Acute vascular rejection. Xentransplantation 1998 Aug; 5 (3):169-75.

6. Patience KC, Takeuchi Y, Weiss RA. Zoonoses in xenotransplantation. Curr Opin Immunol 1998 Oct; 10 (5):539-42.

7. Dorling A, Lechler RI. T-cell-mediated xenograft rejection: Specific tolerance is probably required for long term xenograft survival. Xenotransplantation 5 (4):234-245.

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