Pentoxifylline functions as an adjuvant in vivo to enhance T cell immune responses by inhibiting activation-induced death.
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.
Suresh
Radhakrishnan
R
National Institute of Immunology, Aruna Asaf Ali Road, New Delhi 110067, India.
Vig
Monika
M
Bhatia
Sumeena
S
Goodspeed
Eric P B
EP
John
Beena
B
Kandpal
Usha
U
Srivastava
Smita
S
George
Anna
A
Sen
Ranjan
R
Bal
Vineeta
V
Durdik
Jeannine M
JM
Rath
Satyajit
S
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D003114:Colony-Forming Units Assay; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D018984:Epitopes, T-Lymphocyte / Q000032:analysis; D007114:Immunization; D007156:Immunologic Memory / Q000187:drug effects; D007279:Injections, Subcutaneous; D008213:Lymphocyte Activation / Q000187:drug effects*; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010431:Pentoxifylline / Q000008:administration & dosage* / Q000276:immunology / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology
D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D018984:Epitopes, T-Lymphocyte; D017868:Cyclic AMP-Dependent Protein Kinases; D010431:Pentoxifylline