In patients undergoing hematopoietic stem cell transplantation (HSCT) with HLA-identical donors, genetic polymorphisms result in a mismatch between donors and recipients in their minor histocompatibility antigens (mHAgs), and tumors may also express tumor-associated antigens (TAA) that may not be abundantly present in the donors. Donor T cells can recognize such mHAgs and TAAs as foreign antigens and generate an objective response against hematologic malignancies in a graft-versus-tumor (GVT) effect. However, a major side effect of HSCT occurs when donor T cells are alloreactive against the recipients’ normal cells, leading to graft-versus-host disease (GVHD). The ability to identify T cell clones that are exclusively involved in the GVT or GVHD responses remains elusive. In this study, we looked at clonally-driven CD3+ T cells in patients with hematologic malignancies prior to and after transplantation. We identified Vbeta families of increased expression involved in GVHD or GVT responses, with Vbetas 4, 11, and 23 being associated with GVHD, Vbetas 9, 16, and 20 being associated with GVT, and Vbetas 2, 3, 7, 8, 12, 15, and 17 being involved in GVHD and/or GVT. We were also able to identify some of the Vbeta families that were increased in the peripheral blood at the site of GVHD. Furthermore, one of our twelve patients had donor lymphocyte infusions (DLIs) for treatment of relapse, from which we were able to observe oligoclonal T cells that emerged at the time of post-DLI remission and re-establishment of GVHD.

The goal of hematopoietic stem cell transplantation (HSCT) is to induce graft-versus-tumor effect (GVT), which is the recognition of and response against tumor- associated antigens (TAAs) by donor immune cells to clear the recipient of residual tumor. A complication of HSCT as a treatment for hematologic malignancies is graft-versus-host disease (GVHD), which is the recognition and reactivity of donor immune cells against healthy tissues. As of now, the differentiation between GVHD and GVT effects has been a hindrance to the development of effective therapies against GVHD. Certain T cell clones may induce both GVHD and GVT effects, making targeted therapy of GVHD difficult. This project was aimed to uncover differences at a molecular level of the T cell recognition site that exist between patients with GVHD and those with GVHD-free survival following allogeneic HSCT. We found that there are inherent differences in the T cell receptor at a molecular level between patients experiencing GVHD and those that are GVHD-free, suggesting the ability of T cells to distinguish tumor cells from self cells. In addition, the intention was to reveal differences in proportions of engrafted donor T cells and stem cells and the effects of these proportions on the severity, outcome, and prognosis of GVHD. We additionally found that a lower proportion of stem cells to T cells was associated with the trend of GVHD, while a higher frequency of T cells engrafted into host may indicate resistance to treatment and a poor prognosis. These data suggest that allogeneic HSCT may be improved by optimizing the proportion of T cells to stem cells in the transplant as well as developing targeted therapy against GVHD-associated T cell clones while rescuing GVT-associated T cell clones.