Abstracts (complete list) - Wissenschaft Online

Claudia Stühler, Sarah Lurati, Manik Chatterjee, Ralf C. Bargou, Hermann Einsele, Max
S. Topp
Treatment of T lymphocytes with Hsp90 inhibitors selectively
kills activated cells while preserving viability and
functionality of resting cells
Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality in
patients with hematological malignancies undergoing allogeneic hematopoietic stem cell
transplantation (HSCT). Current treatment of GvHD utilizes immunosuppressive
regimens which put the patient at a high risk of opportunistic infections. Therefore
selective approaches for specific eradication of GvHD-specific T-cells are highly
warranted. Inhibition of heat shock protein 90 (Hsp90) could be one approach, as
Hsp90 aids in the maturation and stabilization of a wide variety of client proteins, some
of which are integral components of signal transduction pathways of activated T-cells.
In the first set of experiments selective upregulation of both Hsp90 subunits in activated
primary T-cells was confirmed and shown to be impeded by application of the Hsp90
inhibitors Geldanamycin and 17-DMAG as well as with siRNA. Addition of Hsp90 inhibitor
to either mitogen-activated T-cells or T-cells activated by allogeneic stimulator cells lead
to preferential eradication of activated cell populations. The preferential killing of only
activated cells could be shown by stimulation of 17-DMAG pretreated mixed lymphocyte
cultures with either autologous APC presenting viral antigens or rechallenge with the
same allogeneic dendritic cells. Whereas virus-specific T-cells could readily be activated,
no activation could be detected in 17-DMAG pretreated T-cell cultures exposed for a
second time to the allogeneic stimulators. Untreated cultures on the other hand
responded to both stimuli. To verify which crucial signalling pathways of activated Tcells
are abrogated in the presence of Hsp90 inhibitors further western blot experiments
were performed.
This experimental data demonstrate that Hsp90 inhibitors can selectively remove
alloreactive T lymphocytes upon activation without compromising the viability and
functionality of the remaining lymphocyte populations including the virus-specific
immune response.