Selective depletion of alloreactive T cells by targeted therapy of heat shock protein 90: a novel strategy for control of graft-versus-host disease

Abstract

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. (Blood.

Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

“…Hence, in vivo-expanded iC9 1 virus-specific T cells may be more resistant to the apoptotic signals generated by iC9 than alloreactive T cells. [34][35][36][37][38][39] Thus, iC9 activation in alloreplete T cells can selectively eliminate the alloreactive component of T cells that cause GVHD, while sparing the virus-reactive subpopulation, even when CID is administered during an active viral infection.…”

Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice

“…Inhibition of Hsp90 may also affect pathways such as Akt, Jak-Stat, Erk1/2, and Lck. 45 Recent studies have suggested that Ezh2 is an important downstream effector of Akt and Jak3 in promoting cancercell proliferation. 46,47 To further prove whether Ezh2 is a major target of AUY922 for reducing GVHD, we transduced WT B6 CD8…”

Haploidentical hematopoietic transplantation: current status and future perspectives

“…T-cell preparations are purged of alloreactive donor T cells by activation in mixed lymphocyte reaction against host stimulators, followed by depletion with immunotoxins, immunomagnetic selection, or FACS, all of which exploit expression of cell surface activation markers (CD25, CD69, CD134, CD137, CD147, and HLA-DR). [59][60][61][62][63] Other methods include FasL-mediated killing of activated T cells, 64 apoptosis induction by heat shock protein 90 (HSP 90), 65 or anergy induction by costimulatory blockade. 66 The anti-CD25 antibody conjugated to ricin toxin was first used in pediatric patients with immune deficiencies.…”