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Pentoxifylline Functions As an Adjuvant In Vivo to Enhance T Cell Immune Responses by Inhibiting Activation-Induced Death¹

Radhakrishnan Suresh^2,*, Monika Vig^2,*, Sumeena Bhatia^*, Eric P. B. Goodspeed, Beena John^*, Usha Kandpal^*, Smita Srivastava^*, Anna George^*, Ranjan Sen, Vineeta Bal^3,*, Jeannine M. Durdik^3, and Satyajit Rath^3,*

^* National Institute of Immunology, New Delhi, India; Department of Biological Sciences, University of Arkansas, Fayetteville, AR 72701; and Rosenstiel Research Center, Brandeis University, Waltham, MA 02254

Modalities for inducing long-lasting immune responses are essential components of vaccine design. Most currently available immunological adjuvants empirically used for this purpose cause some inflammation, limiting clinical acceptability. We show that pentoxifylline (PF), a phosphodiesterase (PDE) inhibitor in common clinical use, enhances long-term persistence of T cell responses, including protective responses to a bacterial immunogen, Salmonella typhimurium, via a cAMP-dependent protein kinase A-mediated effect on T cells if given to mice for a brief period during immunization. PF inhibits activation-mediated loss of superantigen-reactive CD4 as well as CD8 T cells in vivo without significantly affecting their activation, and inhibits activation-induced death and caspase induction in stimulated CD4 as well as CD8 T cells in vitro without preventing the induction of activation markers. Consistent with this ability to prevent activation-induced death in not only CD4 but also CD8 T cells, PF also enhances the persistence of CD8 T cell responses in vivo. Thus, specific inhibition of activation-induced T cell apoptosis transiently during immune priming is likely to enhance the persistence of CD4 and CD8 T cell responses to vaccination, and pharmacological modulators of the cAMP pathway already in clinical use can be used for this purpose as immunological adjuvants.

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