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The efficacy of allogeneic hematopoietic cell transplantation (HCT) in hematologic malignancies can in large part be attributed to a graft-versus-tumor (GVT) effect, by which the donor immune system achieves immunologic control of the tumor. As such, it is the prototype of cellular therapy. The human leukocyte antigen (HLA) system is fundamental to transplant biology. The HLAs are highly polymorphic proteins that have a key role in antigen presentation and immunoregulation. Class I HLAs are expressed on the surfaces of all nucleated cells; class II are expressed on specialized antigen-presenting cells (APCs), such as macrophages, dendritic cells, and B cells.
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Peptides derived from microbes are presented on class I HLAs to CD8+ T cells and result in immunologic destruction of infected cells; class II HLAs are recognized by CD4+ T cells. T-cell activation requires costimulatory signals from the APC, specifically CD80/86 binding to CD28 or LFA-3 binding to CD2 (1). Absence of a costimulatory signal results in T-cell anergy, which is a key mechanism of peripheral immune tolerance to self-antigen in normal immunoregulation. Early posttransplantation, there is a “cytokine storm”; release of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), is induced by tissue damage from the conditioning regimen, activating the host innate immune system (Fig. 16-1). Donor T cells interact with host APCs and recognize foreign peptides; helper T cells produce further cytokines, especially IL-2, and prime host APCs via CD40:CD40L interaction. Differentiation of naïve donor T cells into effector cells subsequently occurs, resulting in immunologic attack on host tissues and the potential development of graft-versus-host disease (GVHD) (2). Increasing numbers of HLA mismatches are associated with higher incidence of GVHD and transplant-related mortality (TRM) (3). However, even in a fully HLA matched HCT, GVHD still occurs due to donor T cells directed against minor histocompatibility antigens (MiHAs), polymorphic peptides displayed on host HLA molecules.
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