Immune Reconstitution/Immunocompetence in Recipients of Kidney Plus Hematopoietic Stem/Facilitating Cell Transplants

Abstract

Nineteen subjects have more than 18 months' follow-up in a phase IIb tolerance protocol in HLA-mismatched recipients of living donor kidney plus facilitating cell enriched hematopoietic stem cell allografts (FCRx). Reduced intensity conditioning preceded a kidney allograft, followed the next day by FCRx. Twelve have achieved stable donor chimerism and have been successfully taken off immunosuppression (IS). We prospectively evaluated immune reconstitution and immunocompetence. Return of CD4 and CD8 T central and effector memory cell populations was rapid. T-cell receptor (TCR) Excision Circle analysis showed a significant proportion of chimeric cells produced were being produced de novo. The TCR repertoires posttransplant in chimeric subjects were nearly as diverse as pretransplant donors and recipients, and were comparable to subjects with transient chimerism who underwent autologous reconstitution. Subjects with persistent chimerism developed few serious infections when off IS. The majority of infectious complications occurred while subjects were still on conventional IS. BK viruria and viremia resolved after cessation of IS and no tissue-invasive cytomegalovirus infections occurred. Notably, although 2 of 4 transiently or nonchimeric subjects experienced recurrence of their underlying autoimmune disorders, none of the chimeric subjects have, suggesting that self-tolerance is induced in addition to tolerance to alloantigen. No persistently chimeric subject has developed donor-specific antibody, and renal function has remained within normal limits. Patients were successfully vaccinated per The American Society for Blood and Marrow Transplantation guidelines without loss of chimerism or rejection. Memory for hepatitis vaccination persisted after transplantation. Chimeric subjects generated immune responses to pneumococcal vaccine. These data suggest that immune reconstitution and immunocompetence are maintained in persistently chimeric subjects.

Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

“…Chimerism was induced in 12 subjects who were successfully withdrawn from immunosuppression [82]. Several cases of serious infectious complications were reported [83]. Remarkably, HSC engraftment was accomplished across (multiple) HLA barriers (HLA match ranging from 1/6 to 5/6) without the occurrence of GVHD.…”

“…Remarkably, HSC engraftment was accomplished across (multiple) HLA barriers (HLA match ranging from 1/6 to 5/6) without the occurrence of GVHD. Chimeric recipients were shown to develop protective immunity in response to vaccination [83], providing preliminary evidence for their immunocompetence. Some patients retained the immune status of the recipient, as shown by retention of the recipient's vaccination status, suggesting that mixed, rather than full chimerism, is present in these individuals.…”

“…Groups from the University of Louisville and Northwestern University have performed combined HLA-mismachted (1-6 mismatches) kidney and HSCT in 19 patients [39,81,82]. Recipients were conditioned with a nonmyeloablative regimen consisting of fludarabine, 2 Gy TBI and posttransplant cyclophosphamide and also received a bioengineered cell product, derived from donor mPBSCs.…”

“…Some patients retained the immune status of the recipient, as shown by retention of the recipient's vaccination status, suggesting that mixed, rather than full chimerism, is present in these individuals. TCR repertoire analysis revealed a diverse T-cell repertoire [83]. Immunol.…”

“…No graft was lost, the white blood cell count remained >500/mm 3 in all patients and no GVHD was observed. Mixed chimerism, in most cases transient, was also induced in a cohort of haplotype-mismatched patients, which required escalating the dose of CD34 + cells and T cells, with immunosuppression withdrawal ongoing at the time of reporting [80].Groups from the University of Louisville and Northwestern University have performed combined HLA-mismachted (1-6 mismatches) kidney and HSCT in 19 patients [39,81,82]. Recipients were conditioned with a nonmyeloablative regimen consisting of fludarabine, 2 Gy TBI and posttransplant cyclophosphamide and also received a bioengineered cell product, derived from donor mPBSCs.…”