ASSOCIATION OF DONOR-DERIVED HOST-REACTIVE CYTOLYTIC AND HELPER T-CELLS WITH OUTCOME FOLLOWING ALTERNATIVE DONOR T-CELL-DEPLETED BONE-MARROW TRANSPLANTATION

Recipients of marrow from alternative donors (unrelated or alh-mismatc hed related donors) have a higher incidence of post-transplant complic ations compared to recipients of marrow from HLA-identical siblings, H LA disparity undetected by routine typing techniques has been suggeste d as one cause for the increased complications observed, Limiting dilu tion analysis (LDA) of donor-derived, host-reactive T cell precursor f requency prior to transplant has been proposed as a surrogate indicato r of underlying HLA disparity which might be used to predict transplan t outcome and aid in donor selection, We compared results of LDA of ho st-reactive IL-2 producing helper T lymphocytes (HTLp) and/or cytolyti c T lymphocytes (CTLp) in 77 alternative marrow donor/recipient pairs with transplant outcome using univariate and multivariate analysis. Al l donor grafts were depleted ex vivo of mature T cells. Median patient age was 15 years (1-53). Donor selection was based on serologic typin g for HLA class I and high resolution oligotyping for HLA-DRB1-DRB5, a nd HLA-DQB1. HLA-A and HLA-B locus antigens were retrospectively defin ed by one dimensional isoelectric focusing (IEF). Cox proportional haz ards regression models were used to assess the impact of frequency and estimated cell dose of CTLp and HTLp on outcome, The CTLp assay was m ost sensitive to HLA-A and HLA-B locus disparity detected by serology or IEF, The HTLp assay detected class I disparity but was most strongl y reactive in the presence of HLA-DRB1 disparity. Univariate analysis indicated a significant association of CTLp frequency and dose with se vere (grades 3-4) acute graft-versus-host disease (GVHD), and of CTLp dose with chronic GVHD. Both assays were associated with survival and neither assay was associated with relapse, After adjustment for other significant covariables including known HLA disparity, the association of CTLp with acute GVHD was lost, however, CTLp frequency and CTLp do se remained associated with survival and HTLp frequency was associated with chronic GVBD. These data support the hypothesis that post-BMT co mplications may be influenced not only by T cell dose but by the allor eactive potential of the cells infused, LDA of alloreactive potential was useful in detecting disparity and in predicting survival or chroni c GVHD in recipients of alternative donor TCD marrow grafts.