*Purpose: We assessed the impact of the hematopoietic cell dose and the immunosuppressive drug (IS) withdrawal on the persistence of mixed chimerism after combined HLA haplo-identical kidney and hematopoietic cell transplantion.

*Methods: Twenty two patients were given combined HLA haplotype matched living related kidney and hematopoietic cell transplants to establish persistent mixed chimerism, and facilitate IS drug withdrawal. Patients were conditioned with total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) after kidney transplantation, and given an infusion of a defined escalating dose of donor CD3+T cells (3 to 100×10^6 cells/kg) and a dose of enriched G-CSF mobilized CD34+ hematopoieic progenitor from the donors.

*Results: There was no correlation between the dose of injected T cells and the persistence of mixed chimerism for at least 1 year. The dose of CD34+ cells varied from 8 to 26×10^6 cells/kg, and a second mobilizing agent, plerixafor, was administered to the last 10 consecutive donors in order to increase the yield of CD34+ cells. All of the latter donors had yields of at least 10×10^6 cells/kg, whereas 5 of 12 donors without plerixafor had yields of less than 10×10^6 CD34+ cells/kg. None of the recipients given less than 10×10^6 CD34 cells/kg developed persistent mixed chimerism for at least 1 year, and about 60% (10/17) of recipients given at least 10×10^6 cells/kg developed persistent mixed chimerism without GVHD. The latter chimeric patients were withdrawn from steroids and mycophenolate mofetil, and were maintained on tacrolimus monotherapy at the end of the first year posttransplant. Persistence of mixed chimerism during the second year was dependent on continuation of tacrolimus monotherapy. Chimerism among T cells at all time points was significantly reduced as compared to all other cell lineages including B cells, NK cells, and granulocytes. The mean levels of T cell chimerism were about 30% below that of B cell chimerism during the first year posstransplant. The recovery of naïve T cells among all T cells was markedly delayed as compared to the recovery naïve B cells among all B cells. Chimerism among CD4+ T cells was confined to the naïve T cells, and almost all memory CD4+ T cells were of recipient origin. In addition, the delayed recovery of naïve T cells during the first year was associated with delayed recovery of the diversity of the T cell repertoire as determined by TCR gene sequencing by RNA seq. The persistence of recipient CD4+ and CD8+ memory T cells was associated with freedom from opportunistic, and chronic viral infections.

*Conclusions: Mixed chimerism for at least 1 year was safely achieved in the HLA haplotype matched patients reduced to tacrolimus monotherapy. The dose of donor CD 34+ cells rather than CD3+ T cell correlated with persistence of mixed chimerism.

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