期刊
ONCOIMMUNOLOGY
卷 5, 期 6, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2016.1146842
关键词
Cytolytic function; Foxp3; graft-versus-leukemia; graft-versus-host disease; regulatory T cells; Treg therapy
资金
- NIH [P30GM103342, P20GM103499]
- MUSC's Office of the Provost
- National Institutes of Health, National Cancer Institute [R01s CA118116, CA169116]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [TL1TR001451, UL1TR001450] Funding Source: NIH RePORTER
Adoptive natural regulatory T cell (nTreg) therapy has improved the outcome for patients suffering from graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (Allo-HCT). However, fear of broad immune suppression and subsequent dampening of beneficial graft-versusleukemia (GVL) responses remains a challenge. To address this concern, we generated alloreactive induced Tregs (iTregs) from resting CD4(+) or CD8(+) T cells and tested their ability to suppress GVH and maintain GVL responses. We utilized major mismatched and haploidentical murine models of HCT with host-derived lymphoma or leukemia cell lines to evaluate GVH and GVL responses simultaneously. Alloreactive CD4(+) iTregs were effective in preventing GVHD, but abrogated the GVL effect against aggressive leukemia. Alloreactive CD8(+) iTregs moderately attenuated GVHD while sparing the GVL effect. Hence, we reasoned that using a combination of CD4(+) and CD8(+) iTregs could achieve the optimal goal of Allo-HCT. Indeed, the combinational therapy was superior to CD4(+) or CD8(+) iTreg singular therapy in GVHD control; importantly, the combinational therapy maintained GVL responses. Cellular analysis uncovered potent suppression of both CD4(+) and CD8(+) effector T cells by the combinational therapy that resulted in effective prevention of GVHD, which could not be achieved by either singular therapy. Gene expression profiles revealed alloreactive CD8(+) iTregs possess elevated expression of multiple cytolytic molecules compared to CD4(+) iTregs, which likely contributes to GVL preservation. Our study uncovers unique differences between alloreactive CD4(+) and CD8(+) iTregs that can be harnessed to create an optimal iTreg therapy for GVHD prevention with maintained GVL responses.
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