Graft-vs-host disease (GVHD), a major complication of allogeneic stem cell transplantation (alloSCT), is a direct result of donor T cells. Elimination of T cells by graft processing can prevent GVHD but this can result in immunodeficiency and elimination of graft-vs.-leukemia (GVL) effects. It is the basic goal of GVHD research- including this proposal-to prevent and/or treat GVHD while maintaining immune reconstitution and GVL. As mature blood components, specifically donor T cells, are an essential therapeutic aspect, alloSCT includes transfusion. Via cell processing, which is typically performed by the Transfusion Medicine service, it should be feasible to engineer and purify the graft to mitigate the ability of T cells to cause GVHD and to still preserve GVL and pathogen protection. As a physician-scientist in the area of Transfusion Medicine it is the goal of the PI and this research project to develop the basic science and preclinical models behind this long-term endeavor. In order to achieve this, a clear understanding of the cellular events and pathophysiology of GVHD and GVL is required. Several years ago our group and others discovered that donor T cells with an """"""""effector mem- or"""""""" phenotype (TEM) were unable to cause murine GVHD. This represents a great therapeutic opportunity, as TEM are readily accessible in human PBL. In addition, if the key properties of TEM were understood, it might be possible to convert other phenotypes of T cells to TEM or to cells with TEM-like qualities, and if such cells were engineered with anti-tumor or anti-viral TCRs they would be less likely to cause GVHD. In order to do this, it is important to understand why TEM do not cause GVHD. Our broad hypothesis is that TEM are intrinsically less able to mediate disease due to: a) less pathogenic effector functions;b) reduced clonally expansion;c) migratory differences;d) greater susceptibility to inhibitory signals;and e) altered interaction with presenting cells in tissues. We further suggest that these differences are less relevant to GVL and pathogen protection, as these do not require the same level of sustained effectors function and expansion. A major barrier to understanding why TEM do not cause GVHD is an inability to track the GVHD-inducing T cells, which are quite rare. To address this, our lab has recently constructed and validated a new model of GVHD in which dis- ease is driven by transfusion of T cells from a TCR transgenic mouse. Recipient mice in this model carry an """"""""antigen transgene"""""""" that causes expression of the target of the TCR at low levels in all tissues, thus serving as a minor histocompatibility Ag. This model reproduces remarkably well the phenotypes and path physiology of GVHD. The system has thus enabled the unprecedented ability to track T cells that are causing disease. It also allows the conversion of T cells with identical origin and TCR into different types, for example """"""""effector mem- ory"""""""" or """"""""central memory,"""""""" and the testing of their GVHD potency. We propose to utilize this new model in Aim 1 to test several hypotheses to explain why TEM are less potent mediators of GVHD and then in Aim 2 to test ap- proaches to engineer TEM for clinical transfusion in order to promote GVL while avoiding GVHD.

Public Health Relevance

Graft-vs.-host disease (GVHD) is a major complication of allogeneic stem cell transplantation (alloSCT), which can cure leukemia, lymphoma, aplastic anemia, and other blood disorders. GVHD, which is caused by T lymphocytes from the donor, is a major source of morbity and mortality and it limits the use of alloSCT. We found that certain types of donor T cells do not cause GVHD, but can be beneficial instead in curing leukemia. Here we are investigating why this is and how to better apply this knowledge to the human clinical setting.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VH-F (50))
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Welniak, Lisbeth A
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Yale University
Schools of Medicine
New Haven
United States
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