Although the paradigm of CD4+ Th1 vs Th2 responses provides a framework for understanding the host immune response, our knowledge of the immunological components that lead to chronic infections vs disease resolution remains incomplete. Experimental infection of mice with the New World parasite L. amazonensis results in persistent infection with a high parasite load and recapitulates many aspects of chronic leishmaniasis in humans. Our long-term goal is to understand how L. amazonensis is able to persist, at high parasite loads, in an immunocompetent host. Understanding this host-parasite relationship will lead to better diagnostic, prognostic, preventative and post-exposure immuno-modulation strategies for many chronic infections in both human and veterinary medicine. Our central hypothesis is that the immune phenotype of chronic L. amazonensis infection reflects immune mechanisms of adaptive tolerance which accounts for the paradox of the presence of antigen-responsive memory CD4+ T cells along with high numbers of L. amazonensis parasites. We have also found the only consistent method to reduce the parasite load to very low levels, resolve the lesion and maintain effective immunity after L. amazonensis challenge is to prime the immune system with a L. major infection. We have demonstrated that L. major-specific CD4+ T cells and L. major-specific B cells, plus immunoglobulins, are necessary for healing L. amazonensis. These studies, in conjunction with those of other investigators, indicate that B cells, much like Th1 vs Th2 CD4+ cells, have the potential to promote or limit cell-mediated immunity depending on parasite species/strain and the unique qualities of the host.
We propose that many chronic infections in both human and veterinary medicine remain difficult to manage clinically or prevent by vaccination as a result, in part, of immunoregulatory events that balance pro-inflammatory effector actions with the protection of organ function. Identifying the biological rules that govern this immune self-regulation is complicated by our inability to comprehend the complex relationships between host-derived immune factors. We propose to use mathematical modeling to build a systems-based model of immune self-regulation. Ultimately, knowledge of the processes that regulate the immune response to persistent antigen will guide progress toward better vaccines and therapies for chronic infectious diseases, autoimmune disease, and cancer.
V.M.D.: University of Pennsylvania, 1989.
M.S.: University of Connecticut, 1985.
Ph.D.: University of Pennsylvania, 1993.
Veterinary Parasitology -- V Pth 376, Veterinary entomology section.
Pathology of Parasitism -- V Pth 660, Instructor in charge.
Mukbel R, C Patten Jr., K. Gibson, M Ghosh, CA Petersen, C. and DE Jones. (In Press) Efficiency of Leishmania amazonensis amastigote killing by macrophages is determined by both nitric oxide and superoxide. The American Journal of Tropical Medicine and Hygiene.
Simutis, F.J., Jones, D.E. and Hostetter, J. 2007. Failure of antigen-stimulated gamma-delta T cells and CD4+ T cells from sensitized cattle to upregulate nitric oxide and mycobactericidal activity of autologous Mycobacterium avium subsp. paratuberculosis-infected macrophages. Veterinary Immunology and Immunopathology. March 15; 116 (1-2): 1-12.
Mukbel, R., Petersen, C.A. and Jones, D.E. 2006. Soluble factors from Leishmania major-specific CD4+ T cells and B cells limit L. amazonensis amastigote survival within infected macrophages. Microbes and Infection; 8; 2546-2555.
Coetzee, J.F., Apley, M.D., Kocan, K.M. and Jones, D.E. 2006. Flow cytometric evaluation of selected antimicrobial efficacy for clearance of Anaplasma marginale in short-term erythrocyte cultures. Journal of Veterinary Pharmacology and Therapeutics; 29; 173-183.
Ramer, A.E., Y. Vanloubbeeck and D.E. Jones. 2006. Antigen-responsive CD4+ T cells from C3H mice chronically infected with Leishmania amazonensis are impaired in their transition to effector phenotype. Infection and Immunity; 74 (3); 1547-1554.
Vanloubbeeck, Y., M. R. Ackermann and D. E. Jones 2005. Late Cutaneous Metastases in C3H SCID Mice Infected with Leishmania amazonensis. Journal of Parasitology 91(1); 226-228.
Simutis, F.J., N.F. Cheville and DE Jones. 2005. Antigen-specific T cell responses and subcutaneous granuloma development during experimental sensitization of bovine calves with Mycobacterium avium subsp. paratuberculosis. American Journal of Veterinary Research; 66(3) 474-482.
Vanloubbeeck Y, AE Ramer and DE Jones. 2004. CD4+ Th1 cells induced by a dendritic cell-based immunotherapy in mice chronically infected with L. amazonensis do not promote healing. Infection and Immunity ; 72, 4455-4463.
Vanloubbeeck Y and DE Jones. 2004. Infection of C3HeB/FeJ mice with Leishmania major protects against subsequent challenge with Leishmania amazonensis. The American Journal of Tropical Medicine and Hygiene; 71(4); 407-411.
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Coinventor on Patent 5,641,497; Gastrointestinal defensins, cDNA sequences and method for the production and use thereof, June 1997.
Recipient of NIH Medical Scientist Training Program grant, 1985-1991.
Veterinary School Honor Society
Phi Zeta, Beta chapter
American Veterinary Medical Association
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