Shared biology of GVHD and GVT effects: potential methods of separation.
The difficult separation of clinical graft-versus-tumor (GVT) effects from graft-versus-host disease (GVHD) reflects their shared biology. Experimental approaches to mediate GVT effects while limiting GVHD include: (1) allograft T cell depletion followed by immune enhancement; (2) modulation of T cell dose or T cell subset composition; (3) donor lymphocyte infusion; (4) reduced-intensity host preparation; (5) modulation of Th1/Th2 and Tc1/Tc2 cell balance; (6) cytokine therapy or neutralization; (7) T regulatory cell therapy; (8) co-stimulatory pathway modulation; (9) chemokine pathway modulation; (10) induction of antigen-specific T cells; (11) alloreactive NK cell therapy; and (12) targeted pharmaceutical inhibition of proteosome, mammalian target of rapamycin, and histone deacetylase pathways. Clearly, a multitude of approaches exist that hold promise for separating GVT effects from GVHD. Future success in this endeavor will require a strong commitment towards translational research and continued advances in cell, vaccine, cytokine, monoclonal antibody, and targeted molecular therapy.
Fowler
Daniel H
DH
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, CRC, 3-East Laboratories, 3-3330, Bethesda, MD 20892-MSC 1203, USA. dhfowler@helix.nih.gov
D016207:Cytokines / Q000037:antagonists & inhibitors / Q000276:immunology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000628:therapy; D020350:Graft vs Tumor Effect / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation; D008212:Lymphocyte Depletion; D017710:Lymphocyte Transfusion; D008297:Male; D009369:Neoplasms / Q000150:complications / Q000276:immunology / Q000628:therapy; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D061988:Proteasome Inhibitors; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation; D014184:Transplantation, Homologous
D016207:Cytokines; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases