The long-term goal for the proposed studies is to improve survival in patients who undergo allogeneic hematopoietic progenitor cell transplantation (HPCT). HPCT recipients will benefit from novel therapies that enhance graft versus tumor (GvT) effects while minimizing graft versus host disease (GvHD). Recent data indicate that """"""""memory"""""""" CD44(high) CD4+ donor T-cells have GvT activity without dose-limiting GvHD. The applicant has developed a novel method of selectively depleting CD44(Iow) and preserving CD44(high) CD4+ T-cells donor T-cells using ex vivo exposure to fludarabine that will be studied with three specific aims: #1: To characterize the GvHD and GvT activity of naive CD44(Iow) versus CD44(high) CD4+ T-cells. The hypothesis is that fludarabine selectively deletes CD44(Iow) naive T-cells via enhanced apoptosis reducing allo-reactive naive T-cells. GvHD and GvT activity of FACS sorted CD44(Iow) and CD44(high) CD4+ T-cell subsets will be compared in allogeneic BMTs. #2: To determine the mechanisms by which fludarabine-treatment leads to reduction in the allo-reactivity of donor T-cells. In vitro and in vivo model systems will test the following hypotheses: 1) reduced synthesis of the pro-inflammatory cytokines following deletion of the CD4(Iow) CD4+ T-cells; 2) reduced homing of allo-reactive T-cells to the gastro-intestinal epithelium; 3) enrichment of regulatory/suppressor T-cells. #3 To determine the ability of CD44(high) CD4+ T-cells to transfer antigen-specific cellular immunity without causing GvHD. The hypothesis is that antigen specific memory T-cells survive fludarabine exposure and proliferate in allogeneic BMT recipients without producing pro-inflammatory cytokines. An established mouse model of CMV infection after allogeneic BMT and CMV peptide-MHC tetramer reagents will be used to measure anti-mCMV donor T-cells. The overall objective of these studies is to develop a novel methods of allograft engineering to improve immune reconstitution and enhance GvT activity without increasing GvHD. Our studies will improve the understanding of the role of donor cells in inducing GvHD and GvT effects after allogeneic HPCT and facilitate development of novel approaches in immunotherapy cancer patients.
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