Journal
BONE MARROW TRANSPLANTATION
Volume 47, Issue 9, Pages 1196-1200Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bmt.2011.237
Keywords
haploidentical SCT; adoptive immunotherapy; photodynamic purging; T-cell alloreactivity; T-cell frequency; limiting-dilution assay
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Funding
- Italian Association for Cancer Research
- Italian Ministry of Further Education
- Italian Ministry of Health
- Leukemia and Lymphoma Society
- European Community 'Allostem' Project [503319]
- National Institutes for Health of the USA [1 PO1 CA 100265-01A1]
- Piero Martino Fellowship for Infectious complications in Hematological Malignancies of the Italian Society of Experimental Hematology
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In adults, one-haplotype-mismatched haematopoietic SCT (haploidentical HSCT) is associated with slow immune recovery due to decaying thymic function and extensive T-cell depletion of the graft. Although essential for preventing GVHD, T-cell depletion underlies the major reasons for transplant failure: leukemia relapse and infections, with infection-related mortality accounting for about 40% of non-leukemic deaths. Adoptive T-cell therapy would be helpful for these patients but to administer it without causing GVHD, alloreactive T cells need to be eliminated from donor T lymphocytes before infusion. In a preclinical study, to address this problem, we determined the efficacy of photodynamic purging of alloreactive T cells, by investigating combinations of parameters in order to achieve maximum allodepletion, preservation of T-regulatory cells and of pathogen and leukemia-specific T-cell responses in donor-vs-recipient MLR. We also needed to identify an optimal method to quantify the Ag-specific T-cell repertoires. Optimal procedures were identified. In particular, we compared limiting-dilution analyses (LDA) of proliferating T cells with H-3-thymidine incorporation by bulk T cells and with flow cytometry CD25 expression, which is accepted as a T-cell activation marker. This study demonstrated that LDA is a reliable, predictable and sensitive method for measuring alloreactive, pathogen-and leukemia-specific T-cell frequencies.
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