COMPOSITE TISSUE TRANSPLANTATION: TOLERANCE THROUGH HEMATOPOIETIC CHIMERISM.

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COMPOSITE TISSUE TRANSPLANTATION: TOLERANCE THROUGH HEMATOPOIETIC CHIMERISM.
D. J. Pidwell, Ph.D. , V. S. Gorantle, M.D. , R. N. Gonzales, M.D. , G. R. Tobin, M.D. , W. C. Breidenbach, M.D. and S. T. Ildstad, M.D. . Jewish Hospital Histocompatibility Lab ; Institute for Cellular Therapeutics ; University of Louisville Plastic Surgery and Louisville KY, 40202, Christine Kleinert Institute .

Widespread application of composite tissue allografts (CTA) has been limited by the need for immunosuppressive agents to prevent graft rejection. Inducing tolerance through hematopoietic stem cell chimerism is one approach to overcome this limitation. However, a number of reports have indicated that chimerism does not uniformly induce tolerance to skin while other reports indicate that lower levels of chimerism may not confer tolerance to CTA. It is critical to clarify these points in order to make tolerance protocols utilizing chimerism applicable in clinical CTA. We have tested whether donor-specific CTA are permanently accepted in MHC and minor-antigen disparate rats conditioned with 1100cGy total body irradiation and transplanted with αβ/γδ T cell-depleted bone marrow (BM). We also evaluated the influence of lineage production and level of chimerism on graft acceptance. All chimeras (n=9) demonstrated 51-99% donor class I⁺PBMC 28 days post-BMT. Chimeras were transplanted with irradiated donor-type limbs 76-93 days post BMT. All components of the limbs, including skin, have survived for 52-292 days. Chimeras were monitored monthly for multilineage chimerism. All demonstrated production of T cells (47-99% donor), B cells (67-100% donor), and NK cells (79-100% donor). We conclude that hematopoietic chimerism can induce tolerance to CTA including skin. Survival of various components of the graft may vary based on 1) conditioning regimen used prior to BMT 2) cellular composition of the BM preparation used to induce chimerism or 3) the cell lineage composition of the donor chimerism. Experiments are ongoing to define the influence of these factors on survival of graft components and to define the minimum percent donor chimerism required for tolerance to CTA.