The goal of this project was to develop a tolerance induction protocol for MHC 1-haplotype mismatched kidney transplants (txs) in a rhesus macaque model. The chimeric state was achieved using a new post-kidney tx non-myeloablative, helical tomotherapy-based total lymphoid irradiation (TLI)-based conditioning regimen followed by donor mobilized peripheral blood-CD34+ hematopoietic stem cell (HSC)/T cell (CD3+) infusions. A series of 18 txs with (n=11) and without (n=7) donor HSC infusions were performed. All animals underwent immunosuppression (IS) withdrawal and were followed for rejection. We determined the proportion of recipients that achieved chimerism and that could be withdrawn from all IS for greater than 3 years. Mixed chimerism in the recipient was assessed by quantifying the proportion of donor/recipient DNA, using STR, in various immune cellular lineages circulating within the peripheral blood and according to the duration of the mixed chimerism post-tx. There were 11 kidney+HSC txs. Two achieved chimerism for at least 3 months and both are long-term tolerant survivors (alive and off IS for more than 3 years). Nine animals in the kidney+HSC group did not achieve chimerism and all lost the allografts during the IS weaning or before. All animals in the kidney tx-alone control group lost the kidney with one having prolonged graft survival without IS, but eventually succumbed to chronic antibody mediated rejection. Development of DSA, primarily against Class II MHC, was associated with lack of mixed chimerism. When this tolerance induction protocol resulted in chimerism operational tolerance was achieved. However, challenges remain to enhance the frequency of achieving chimerism, and future studies will include modifications of the conditioning regimen to minimize development of DSA and engraftment syndrome.

CITATION INFORMATION: Kaufman D., Haynes L., Hematti P., Burlingham W., Forest L., Post J., Redfield R., Fernandez L., D'Alessandro A., Haynes J., Jensen K., Strober S. Tomotherapy and Donor Hematopoietic Cells for Tolerance to Kidney Transplants in Rhesus Macaques Am J Transplant. 2017;17 (suppl 3).

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