Therapeutic glucocorticoid-induced TNF receptor-mediated amplification of CD4+ T cell responses enhances antiparasitic immunity.

Abstract

Chronic infectious diseases and cancers are often associated with suboptimal effector T cell responses. Enhancement of T cell costimulatory signals has been extensively studied for cancer immunotherapy but not so for the treatment of infectious disease. The few previous attempts at this strategy using infection models have lacked cellular specificity, with major immunoregulatory mechanisms or innate immune cells also being targeted. In this study, we examined the potential of promoting T cell responses via the glucocorticoid-induced TNF receptor (GITR) family-related protein in a murine model of visceral leishmaniasis. GITR stimulation during established infection markedly improved antiparasitic immunity. This required CD4(+) T cells, TNF, and IFN-gamma, but crucially, was independent of regulatory T (Treg) cells. GITR stimulation enhanced CD4(+) T cell expansion without modulating Treg cell function or protecting conventional CD4(+) T cells from Treg cell suppression. GITR stimulation substantially improved the efficacy of a first-line visceral leishmaniasis drug against both acute hepatic infection and chronic infection in the spleen, demonstrating its potential to improve clinical outcomes. This study identifies a novel strategy to therapeutically enhance CD4(+) T cell-mediated antiparasitic immunity and, importantly, achieves this goal without impairment of Treg cell function.

• Authors: Ashraful Haque, Amanda C Stanley, Fiona H Amante, Fabian de Labastida Rivera, Yonghong Zhou, Rachel D Kuns, Vanessa Yardley, Shimon Sakaguchi, Geoffrey R Hill, Christian R Engwerda
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 184 Issue 5 Pg. 2583-92 (Mar 01 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20139272 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antiprotozoal Agents
• Glucocorticoid-Induced TNFR-Related Protein
• Receptors, Nerve Growth Factor
• Receptors, Tumor Necrosis Factor
• Tnfrsf18 protein, mouse
• Tumor Necrosis Factor-alpha
• Interferon-gamma
• Antimony Sodium Gluconate

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, immunology)
• Antimony Sodium Gluconate (administration & dosage)
• Antiprotozoal Agents (administration & dosage)
• Apoptosis (immunology)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• CD8-Positive T-Lymphocytes (cytology, immunology, metabolism)
• Drug Synergism
• Female
• Glucocorticoid-Induced TNFR-Related Protein
• Immunity, Cellular (immunology)
• Interferon-gamma (metabolism)
• Leishmania donovani (drug effects, growth & development, immunology)
• Leishmaniasis, Visceral (drug therapy, immunology, parasitology)
• Liver (immunology, metabolism, parasitology)
• Liver Diseases, Parasitic (immunology, metabolism, parasitology)
• Male
• Mice
• Mice, Inbred C57BL
• Receptors, Nerve Growth Factor (immunology, metabolism)
• Receptors, Tumor Necrosis Factor (immunology, metabolism)
• T-Lymphocytes, Regulatory (immunology, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)