Alloreactive and XXXX -reactive T cells are preferentially derived from naive precursors in healthy donors: implications for immunotherapy with memory T cells.

@entity1 @entity404 @entity1196 @entity1778 @entity2132 @entity2149 @entity9350 @entity405
BACKGROUND: HLA mismatch antigens are major targets of alloreactive T cells in HLA-incompatible stem-cell transplantation, which can trigger severe @entity2132 and reduce survival in transplant recipients. Our objective was to identify T-cell subsets with reduced in vitro reactivity to allogeneic HLA antigens. DESIGN AND METHODS: We sorted @entity404 and @entity405 T-cell subsets from peripheral blood by flow cytometry according to their expression of naive and memory markers CD45RA, CD45RO, @entity1196 , and @entity9350 . Subsets were defined by a single marker to facilitate future establishment of a clinical-grade procedure for reducing alloreactive T-cell precursors and @entity2132 . T cells were stimulated in mixed lymphocyte reactions against HLA-deficient K562 cells transfected with single @entity2149 /-C/-DR/-DQ mismatch alleles. Alloreactivity was measured by interferon-y spot production and cell proliferation. RESULTS: We observed that allogeneic HLA-reactivity was preferentially derived from subsets enriched for na  ve T cells rather than memory T cells in healthy donors, irrespective of the HLA mismatch allele. This separation was most efficient if CD45RA (versus other markers) was used for sorting. The numbers of allogeneic HLA-reactive effector cells were in median 7.2-fold and 16.6-fold lower in CD45RA(neg) memory @entity405 and @entity404 T cells than in entire @entity405 and @entity404 T cells, respectively. In contrast, proliferation of memory T cells in response to allogeneic HLA was more variably reduced ( @entity405 ) or equivalent ( @entity404 ) when compared to that of na  ve T cells. We also demonstrated in HLA-matched donor- @entity1 pairs that @entity1778 -reactive @entity405 cytotoxic T-lymphocytes were mainly derived from subsets enriched for na  ve T cells compared to memory T cells. CONCLUSIONS: Memory T-cell subsets of most healthy individuals showed decreased allogeneic HLA-reactivity, but lacked significant anti- @entity1778 responses in vitro. The clinical use of memory or na  ve-depleted T cells might be beneficial for HLA-mismatched @entity1 at high risk of @entity2132 and low risk of @entity1778 relapse. Preferred allografts are those which contain @entity1778 -reactive memory T cells. Alternatively, replenishment with @entity1778 -reactive T cells isolated from na  ve subsets is desirable.
