New Developments in Allotransplant Immunology

Abstract

After allogeneic stem cell transplantation, the establishment of the donor's immune system in an antigenically distinct recipient confers a therapeutic graft-versus-malignancy effect, but also causes graft-versus-host disease (GVHD) and protracted immune dysfunction. In the last decade, a molecular-level description of alloimmune interactions and the process of immune recovery leading to tolerance has emerged. Here, new developments in understanding alloresponses, genetic factors that modify them, and strategies to control immune reconstitution are described.In Section I, Dr. John Barrett and colleagues describe the cellular and molecular basis of the alloresponse and the mechanisms underlying the three major outcomes of engraftment, GVHD and the graft-versus-leukemia (GVL) effect. Increasing knowledge of leukemia-restricted antigens suggests ways to separate GVHD and GVL. T cellsThe alloresponse segregates into induction, expansion, and effector phases. In the induction phase, donor CD8 and CD4 T cells interact with peptide antigens complexed with major histocompatibility complex (MHC) class I and II molecules, respectively, on antigen-presenting cells (APCs) of the recipient. The signal given by the MHC through the T-cell receptor (TCR) and CD3, CD4, or CD8 provides the first signal for Tcell activation. A full T-cell response, leading to proliferation of effector cells, requires a second signal delivered by interaction by costimulatory molecules such as CD80 and CD86 on the APCs and CD28 on the lymphocyte surface. During the expansion phase, T cells proliferate, particularly under the influence of growth factors interleukin (IL)-2 and IL-12. The milieu in which T cells expand determines whether they assume the characteristics of T helper (Th) or T cytotoxic (Tc) type 1, or Th/Tc type 2 cells, which have distinct proor antiinflammatory functional properties, respectively.

T-cell and natural killer cell therapies for hematologic malignancies after hematopoietic stem cell transplantation: enhancing the graft-versus-leukemia effect

“…Studies have suggested that expansion of leukemia-associated antigenspecific T cells in the peripheral blood of patients after allogeneic HSCT contribute to the GVL effect. 32,33 Leukemia-associated antigens include an eclectic mix of proteins seen in hematologic malignancies, 18 including cancer/testis antigens such as MAGE A3, developmental proteins such as WT1, and prosurvival/antiapoptotic proteins such as survivin. Several studies have shown that T cells targeting leukemia-and lymphoma-associated antigens can be generated from donors' and patients' periph-…”

A high proportion of donor CD4+ T cells expressing the lymph node-homing chemokine receptor CCR7 increases incidence and severity of acute graft-versus-host disease in patients undergoing allogeneic stem cell transplantation for hematological malignancy

“…Donor-derived mature T cells are involved in engraftment, graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) activity, 1 and thus play a major role in determining clinical outcome. However, separation of the detrimental and beneficial effects conferred by donor-derived T cells remains an elusive clinical goal.…”

Lymphocyte subsets recovery following allogeneic bone marrow transplantation (BMT): CD4+ cell count and transplant-related mortality

“…10 It may be associated with acute GvHD (aGvHD) and chronic GvHD (cGvHD) as both have a negative impact on immune reconstitution. 11,12 Moreover, the age of recipients affects both CD4 þ recovery and response to mitogens. [13][14][15][16][17] It has been suggested that reconstitution and maintenance of effective T-cell immunity after HSCT is dependent on education of T-cell precursors in the thymus.…”