David H. Sachs | Massachusetts General Hospital | Boston, MA
A. Benedict Cosimi | Massachusetts General Hospital | Boston, MA
Massachusetts General Hospital | Boston, MA
ITN010ST
Completed
Studies from our laboratories over the past 15 years have demonstrated in several preclinical animal models that long-term tolerance to organ allografts can be achieved through the induction of mixed lymphohematopoietic chimerism. The present proposal is designed to extend these studies to a clinical protocol for renal transplantation in patients with end-stage renal failure.
Basis/Rationale: We have previously demonstrated in monkeys that a non-myeloablative conditioning regimen achieved transient mixed lymphohematopoietic chimerism and long-term renal allograft survival in full MHC mismatches in >70% of recipients. Our recent clinical studies have demonstrated efficacy in achieving similar mixed chimerism using a modified preparative regimen for the treatment of refractory lymphomas. In a related study, a combination of this regimen with renal transplantation from HLA-identical siblings has resulted in the successful treatment of three patients suffering from myeloma and renal failure.
Clinical Protocol Summary: We propose initially to treat 10 adult patients in end-stage renal failure with an available living related donor, mismatched for one HLA haplotype and not showing evidence of presensitization. Recipients will receive Cyclophosphamide, 60 mg/kg on days –5 and –4, MEDI-507, 0.1 mg/kg on day –2 and 0.6 mg/kg on days –1, 0 and +1, and 7 Gy thymic irradiation on day -1. On day 0, they will receive donor bone marrow (>2xl0^8 nucleated cells/kg) and a donor kidney transplant. Post-transplant, patients will receive a standard dose of cyclosporin for 60 days, followed by tapering doses over the next month.
Significance: Induction of transplantation tolerance has the potential to provide the following benefits to the renal transplant recipient:
Mechanistic Studies: As part of the trial, the following studies will be conducted:
When sufficient T cell numbers have recovered, ELISPOT and intracellular cytokine staining assays will be performed to measure cytokine production in response to donor, host and third party antigens. In addition, TREC analyses of sorted CD4+ and CD8+ populations will be used as a measure of thymic recovery.
Porcheray F, Wong W, Saidman Sl, De Vito J, Girouard TC, Chittenden M, Shaffer J, Tolkoff-Rubin N, Dey BR, Spitzer TR, Colvin RB, Cosimi AB, Kawai T, Sachs DH, Sykes M, Zorn E (2009). B-cell immunity in the context of T-cell tolerance after combined kidney and bone marrow transplantation in humans. Am J Transplant, 9 (9), 2126-35.
DOI:
http://dx.doi.org/10.1111/j.1600-6143.2009.02738.x,
PMID:
19624570
,
PMCID:
PMC2837587
,
PubMed,
ReprintKawai, T, Cosimi AB, Spitzer TR, Tolkoff-Rubin, N, Suthanthiran M, Saidman Sl, Shaffer J, Preffer FI, Ding R, Sharma V, Fishman JA, Dey B, Ko DSC, Hertl M, Goes NB, Wong W, Williams WW, Colvin RB, Sykes M, Sachs DH (2008). HLA-Mismatched renal transplantation without maintenance immunosuppression. N Engl J Med, 358 (4), 353-61.