Treatment of solid tumors should obligatorily be combined with the in vivo codepletion of tumor-protecting, CD8+/HLA-DR(+)-suppressor T cells by alloreactive donor T cells whose preprogrammed cell death allows a high GvL-effect before GvHD can be established. Results of animal experiments, including more than 6000 mice.
The FACS-analysis of diseases as different as cancer, autoimmune disorders and chronic (retro)viral infections, including HIV-infection, shows -at least temporarily- a common feature of lymphocyte hyperactivation, characterized by cellular activation markers (HLA-DR, CD26, CD38, CD69, CD2R and/or CD30), as well as by solubilized membrane structures, such as beta-2m, sICAM-I, sIL-2R/sCD25, sCD8, and by some oversecreted immunocyte products (e.g. neopterin, lysozyme and/or cathepsin D). We tested two potential approaches to down-regulate the pathologically elevated CD8+ and HLA-DR+ T cells: (a) In animal model, we tested the sensibility of these, disease inducing and maintaining T cell subsets to in vitro pretreated (cell death preprogrammed) semi-syngeneic and allogeneic donor T cells in tumor-bearing mice. (b) In the first clinical study, we used a novel combination of FDA-approved drugs which inhibits Ca(2+)-influx and concomitantly down-regulates cytosolic cAMP in patient's overstimulated immunocompetent cells. We could achieve a 94.6-100% long-term survival in tumor-bearing mice. In patients, large primary tumors and large metastases shrinked by 80-85% and small metastases disappeared completely. Since in HIV-infected persons, the increased number of HLA-DR+ CD38+T (T8) cells is associated with a fall in CD4-level and with development of AIDS, we are looking for the elimination of these HLA-DR+ targets by our novel technique in two AIDS-simulating (FIV/FeLV and SIV) animal models.
Leskovar
P
P
Biochemical Research Laboratory, School of Medicine, Technical University of Munich, Germany.
Bielmeier
J
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D017382:Reactive Oxygen Species; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology*; D014407:Tumor Cells, Cultured
D006684:HLA-DR Antigens; D017382:Reactive Oxygen Species