Selective depletion of alloreactive T cells by targeted therapy of heat shock protein 90: a novel strategy for control of graft-versus-host disease.
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients with hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation. Current treatment of GVHD relies on immunosuppressive regimens, considerably increasing the incidence of opportunistic infections. As T cells mediate both GVHD as well as protection against viral infections and the malignant disease, strategies to selectively target host-reactive T cells without impairing pathogen- and disease-specific immunity are highly warranted. Activation of T cells is accompanied by increased expression of the chaperone heat shock protein of 90 kDa (Hsp90), which stabilizes several key signaling pathways crucial for T-cell activation. In this study, selective targeting of Hsp90 in activated T lymphocytes with pharmacologic inhibitors already applied successfully in anticancer therapy resulted in induction of apoptosis predominantly in activated cells. Moreover, if T cells were stimulated with allogeneic dendritic cells, alloreactive T cells were selectively eliminated. In contrast, third party reactions including antiviral T-cell immunity were quantitatively and functionally fully preserved. These data suggest that Hsp90 represents a novel target for selective depletion of alloreactive T cells, and provide the rationale for application of Hsp90 inhibitors as potential approach to selectively prevent and treat GVHD in hematopoietic stem cell transplantation recipients without impairing pathogen- and disease-specific T-cell immunity.
Stuehler
Claudia
C
Department of Internal Medicine II, Division of Hematology, University Hospital of Wuerzburg, Wuerzburg, Germany.
Mielke
Stephan
S
Chatterjee
Manik
M
Duell
Johannes
J
Lurati
Sarah
S
Rueckert
Florian
F
Einsele
Hermann
H
Bargou
Ralf C
RC
Topp
Max S
MS
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007519:Isoantigens / Q000276:immunology; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion / Q000379:methods*; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014780:Viruses / Q000276:immunology
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D007519:Isoantigens; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C112765:tanespimycin