Volume 13 Supplement 2

Kitasato Symposium 2011: Translational prospects for cytokines in 2011

Open Access

Tregs combined with mature donor T cells hasten immune reconstitution without triggering GvHD in HLA haploidentical transplantation

  • Mauro Di Ianni1, 2,
  • Franca Falzetti1 and
  • Massimo F Martelli1
Arthritis Research & Therapy201113(Suppl 2):O6

DOI: 10.1186/ar3410

Published: 16 September 2011

Haploidentical transplantation, with extensive T cell depletion to prevent GvHD, is associated with a high incidence of infection-related deaths. The key challenge is to improve immune recovery with allogeneic donor T cells without triggering GvHD. As T regulatory cells (Tregs) controlled GvHD in preclinical studies, the present phase I/II clinical trial evaluated the impact of early infusion of donor CD4/CD25+ Tregs, followed by an inoculum of donor mature T cells (Tcons) and positively immunoselected CD34+ cells. Twenty-eight patients (median age 41, range 21-60) were enrolled from September 2008 onwards; 22 had AML (10 in CR1 at high risk, 10 in ≥CR2 and 2 in relapse), 5 had ALL (4 in CR1; 1 in relapse) and 1 had high grade NHL in relapse. Conditioning was: 8 Gy single fraction TBI, thiotepa (4 mg/kg × 2), fludarabine (40 mg/m2 × 5), cyclophosphamide (35 mg/kg × 2). All patients received immunoselected Tregs (CliniMACS, Miltenyi Biotec) (23/28 2 × 106/kg bw; 5/28 4 × 106/kg bw) and 4 days later positively immunoselected CD34+ cells (median 8.2 × 106/kg bw, range 5.0-19.1) together with Tcons (4/28 0.5 × 106/kg bw; 17/28 1 × 106/kg bw; 5/28 2 × 106/kg bw; 2/28 did not receive Tcons). CD4/CD25+ Tregs (purity 92.7 ± 2.1) consisted of 33.6% ± 13.1 CD25high; 58.1% ± 6.6 CD25int; 5.8% ± 2.5 CD25low; 65.7% ± 11.8 FoxP3; 17.4% ± 7.2 CD127 (mean ± SD). No GvHD prophylaxis was administered. 26/28 patients engrafted. No GvHD developed in 24/26 patients, 2 developed ≥ grade II GvHD. Ten patients died (3 VOD, 2 fungal pneumonia, 1 bacterial sepsis, 1 CNS aspergillosis, 1 systemic toxoplasmosis, 1 adenoviral infection, 1 MOF). CD4 and CD8 counts reached, respectively, 50/μL medianly on days 34 (range 19-63 days) and 24 (range 15-87); 100/μL medianly on days 47 (range 28-100 days) and 34 (range 19-95); 200/μL on days 70 (range 41-146 days) and 61 (range 21-95). A wide T-cell repertoire developed rapidly with high frequencies of specific CD4+ and CD8+ for opportunistic pathogens. Episodes of CMV reactivation were significantly fewer than after our "standard haplo" transplants. In KIR ligand-mismatched transplants, speed of NK cell reconstitution/maturation and size of donor vs recipient alloreactive NK cell repertoires were preserved. In conclusion, in the setting of haploidentical transplantation infusion of Tregs makes administration of a high dose of T cells feasible for the first time. This strategy provides a long-term protection from GvHD and robust immune reconstitution.

Authors’ Affiliations

(1)
Hematology and Clinical Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia
(2)
Immunology Department, Weizmann Institute of Science

Copyright

© BioMed Central Ltd 2011

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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