Immune responses are dependent on the coordinated movement of leukocytes from sites of antigen deposition, to secondary lymphoid organs and to sites of infection or inflammation. Chemokines play a critical role in this process by directing leukocyte trafficking throughout the body. Although it is well known that leukocytes express chemokine receptors and can migrate directionally in response to chemokine gradients, the molecular mechanism(s) that control chemokine receptor responses are still largely unknown. CD38, an ADP-ribosyl cyclase, that catalyzes the production of the calcium-mobilizing metabolite cyclic ADP-ribose (cADPR), appears to be a critical regulator of chemokine receptor signaling and leukocyte trafficking. We observed that neutrophil migration is impaired in CD38-deficientmice resulting in attenuated and reduced inflammatory responses. We also found that the cADPPR produced byCD38 modulates calcium mobilization in neutrophils that have been activated with inflammatory chemoattractants such as peptides derived from bacteria and viruses. Furthermore, we showed that cADPR-specific antagonists block the migratory response of neutrophils to these peptides. The data suggest that small molecule inhibitors of CD38could potentially be used to block neutrophil-dependent inflammatory responses. Recently, we observed that the migratory response of dendritic cells is also impaired in CD38 deficient mice. Specifically, we found that CD38-deficient dendritic cells cannot migrate in response to ELC or SLC, chemokines that direct dendritic cells to migrate from sites of damage or injury to lymphoid tissues. This impaired chemotactic response observed inCD38-deficient dendritic cells results in inefficient T cell priming and significantly reduced T cell-dependent immune responses. Based on our previous data, we now hypothesize that CD38, through its production of cADPR, regulates cell-dependent immune responses by modulating the migration of dendritic cells. To test this hypothesis we have proposed the following Specific Aims: (1) we will determine whether CD38 regulates migration of all mature dendritic cell subsets to ELC or SLC, (2) we will determine whether CD38 regulates the migration of dendritic cells to inflammatory chemoattractants and (3) we will determine whether cADPR production by CD38 controls dendritic cell trafficking in vivo. These experiments will validate whether CD38 antagonists have the potential to be used as immunosuppressive agents that attenuate immune responses by modulating leukocyte trafficking.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057996-02
Application #
6879620
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2004-04-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$350,000
Indirect Cost
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
020658969
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983
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du Pré, M Fleur; van Berkel, Lisette A; Ráki, Melinda et al. (2011) CD62L(neg)CD38? expression on circulating CD4? T cells identifies mucosally differentiated cells in protein fed mice and in human celiac disease patients and controls. Am J Gastroenterol 106:1147-59
Mayo, Lior; Jacob-Hirsch, Jasmine; Amariglio, Ninette et al. (2008) Dual role of CD38 in microglial activation and activation-induced cell death. J Immunol 181:92-103
Guedes, Alonso G P; Jude, Joseph A; Paulin, Jaime et al. (2008) Role of CD38 in TNF-alpha-induced airway hyperresponsiveness. Am J Physiol Lung Cell Mol Physiol 294:L290-9
Partida-Sanchez, Santiago; Gasser, Andreas; Fliegert, Ralf et al. (2007) Chemotaxis of mouse bone marrow neutrophils and dendritic cells is controlled by adp-ribose, the major product generated by the CD38 enzyme reaction. J Immunol 179:7827-39
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Partida-Sanchez, Santiago; Rivero-Nava, Laura; Shi, Guixiu et al. (2007) CD38: an ecto-enzyme at the crossroads of innate and adaptive immune responses. Adv Exp Med Biol 590:171-83
Guedes, Alonso G P; Paulin, Jaime; Rivero-Nava, Laura et al. (2006) CD38-deficient mice have reduced airway hyperresponsiveness following IL-13 challenge. Am J Physiol Lung Cell Mol Physiol 291:L1286-93
Johnson, James D; Ford, Eric L; Bernal-Mizrachi, Ernesto et al. (2006) Suppressed insulin signaling and increased apoptosis in CD38-null islets. Diabetes 55:2737-46
Kuhn, Isabelle; Kellenberger, Esther; Rognan, Didier et al. (2006) Redesign of Schistosoma mansoni NAD+ catabolizing enzyme: active site H103W mutation restores ADP-ribosyl cyclase activity. Biochemistry 45:11867-78

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