Induction of immunologic tolerance for allogeneic hematopoietic cell transplantation.
The ability to achieve complete hematopoietic engraftment in the allogeneic setting without intensive myeloablative chemotherapy will have a profound effect on the practice of allogeneic hematopoietic cell transplantation (HCT). Novel methods to induce antigen-specific T-cell tolerance provide promise to ensure engraftment and reduce GVHD without producing generalized and other toxicities caused by myeloablative conditioning regimens. Compelling experimental evidence indicates that the antigen receptors on T-lymphocytes have dual potential to transmit crucial activation signals for initiating immune responses and to discharge equally potent inactivating signals to abort or inhibit immune responses. Many events impact on this fundamental decision-making process and one of the great challenges for modern immunology is to decipher the molecular wiring that integrates and converts the extrinsic and intrinsic variables into positive or negative cellular responses termed immunity and anergy, respectively. Our currently expanding understanding of the biochemical and molecular basis of T-cell anergy provides great promise to improve our ability to design novel clinical therapeutic approaches in order to induce antigen-specific tolerance in vivo. Importantly, strategies now exist to segregate graft versus tumor (GVT) effects from GVHD. Therefore, achievement of limited and specific tolerance to host alloantigens by selectively inactivating the indicated subsets of alloantigen-specific T-lymphocytes will prevent GVHD but retain the GVT effect of the graft. Such treatment approaches will expand the donor pool, because they will allow transplantation between individuals with increasing human leukocyte antigen (HLA) disparity, enable reduction of the need for non-specific immunosuppression, and reduce the risk of opportunistic infections and relapse of leukemia.
Appleman
Leonard J
LJ
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Tzachanis
Dimitrios
D
Grader-Beck
Thomas
T
Van Puijenbroek
Andre A F L
AA
Boussiotis
Vassiliki A
VA
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D018122:B7-1 Antigen / Q000502:physiology; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000502:physiology; D019013:CD40 Antigens / Q000502:physiology; D023201:CD40 Ligand / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology; D017635:Clonal Anergy; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006086:Graft vs Host Disease / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation; D006648:Histocompatibility; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology; D007165:Immunosuppression Therapy / Q000379:methods*; D008212:Lymphocyte Depletion; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000502:physiology
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D025521:Tumor Suppressor Proteins; D023201:CD40 Ligand; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000069594:Abatacept