Induction of acute graft vs. host disease in lymphopenic mice

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially life-saving treatment for refractory/relapsing hematological malignancies, blood disorders or autoimmune diseases. However, approximately 40-50% of patients undergoing allogeneic HSCT will develop a multi-organ, inflammatory disorder called acute graft vs. host disease (aGVHD). Experimental and clinical studies suggest that intestinal injury due to toxic, pre-transplant conditioning protocols (e.g. lethal irradiation and/or chemotherapy) may play a major role in the development of aGVHD. However, recent studies from our laboratory suggest that this may not be the case. The objective of this study was to quantify and compare the onset and severity of aGVHD induced by the adoptive transfer of allogeneic T cells into untreated lymphopenic mice. Four million allogeneic or syngeneic CD4⁺CD62L⁺CD25^- T cells were transferred (i.p.) into NK cell-depleted RAG1^-/- mice or RAG2^-/-IL2rγ^-/-double knock-out (DKO) mice and assessed daily for signs of aGVHD. We found that adoptive transfer of allogeneic but not syngeneic T cells into NK cell-depleted RAG1^-/- or DKO mice induced many of the clinical and histological features of aGVHD including weight loss, inflammatory cytokine production and tissue inflammation. In addition, adoptive transfer of allogeneic T cells into each recipient induced severe anemia as well as dramatic reductions in bone marrow and spleen cellularity. Taken together, we conclude that allogeneic CD4⁺ T cells are both necessary and sufficient to induce aGVHD in lymphopenic recipients in the absence of toxic, pre-transplant conditioning.