Research
In vitro allodepletion for the prevention of graft-versus-host disease
Allogeneic stem cell or bone marrow transplantation is an effective treatment in several types of hematolymphoid tumors and can result in long-term remission in otherwise incurable lymphomas and leukemia. Graft-versus-Host Disease (GvHD) is a major cause of transplant-related morbidity and mortality in recipients of allogeneic hematopoietic stem cell transplantation. As GvHD is mediated predominantly by alloreactive donor T-cells, selective allodepletion from the graft may alleviate GvHD, while potentially maintaining other advantages conferred by donor T-cells, such as graft survival, antiviral immunity and graft-versus-leukemia effect. We have evaluated the ability of methotrexate, a clinically approved anti-metabolite drug, to deplete alloreactive T-cells in HLA-mismatched mixed lymphocyte reactions (MLR). We observed that methotrexate could inhibit the proliferation of alloreactive T-cells in primary in vitro MLR. On re-exposure of methotrexate-treated cells to the same allostimulus, a significant reduction in the alloreactive immune response was observed, while responses to third party allostimuli and viral antigens were preserved. Thus, our results provide pre-clinical evidence that in vitro methotrexate treatment results in specific allodepletion and may be used as an effective agent for preventing GvHD. We are now in the process of testing the effectivity of this approach in haploidentical MLR, with the intent to scale up the process for clinical testing.
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Sathe, A., Ortega, S., Mundy, D., Collins, H., Karandikar, N. (2007) http://www.bbmt.org/article/S1083-8791(07)00122-X/abstract. Biology of Blood and Marrow Transplantation 13:6, 644-654.