Acute Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Although this process is thought to consist of several phases, T-cell activation plays a critical role in the pathogenesis of acute GVHD. To become efficient effectors, T-cells require additional costimulation after T-cell receptor signaling. A number of molecules are involved in costimulation of T-cells such as CD28, CD40L, CD30, OX40, 4-1BB, ICOS, and LIGHT. The system is regulated by inhibitory molecules, CTLA-4, and PD-1. There is experimental evidence that those molecules are implicated in the pathogenesis of GHVD. We describe how these molecules are involved in acute GVHD and how the blockade of costimulatory molecules may have potential implications for the treatment of patients with acute GVHD. 1. Introduction Acute graft-versus-host disease (GVHD) remains the most important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation [1]. The recent advances in the pathogenesis of this complication have not been fully translated into an improved treatment for the patients. Only a few immunosuppressive agents are available for the treatment of acute GVHD and thus, new, more selective treatments are needed. Acute GVHD is an immune-mediated disease that results from a complex interaction between immune cells from both, the donor, and recipient. The pathophysiology of this process is thought to consist of several phases: ( ) priming of the immune response through the conditioning treatments that induce inflammation, and secondary activation of antigen presenting cells (APCs) and T-cells, ( ) activation of T-cells which leads to an expansion of effector cells, and finally, ( ) trafficking of activated T-cells to target tissues where inflammation and tissue destruction occurs [1]. Donor-derived T-cells are considered to be the main effector cells mediating acute GVHD. Donor T-cells are able to recognize HLA disparities between the donor and recipient, which is directly related to the development of acute GVHD. Furthermore, recipients of HLA identical transplants can still develop acute GVHD due to differences in the so-called minor histocompatibility antigens [2]. T-cell activation in response to an alloantigen requires two stimulatory signals [3]. The first signal happens through the T-cell receptor (TCR), which recognizes the antigen and is HLA restricted. This signal is necessary but not sufficient to induce a full T-cell activation. Signal 2, known as costimulation, is necessary to induce T-cell
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