NICHOLAS M. PONZIO Professor •  B.A. Seton Hall University •  M.S. Seton Hall University •  Ph.D. SUNY Downstate Medical Center Research Interests Ongoing research projects in the Ponzio laboratory are in the areas of cellular/molecular immunology related to: •  development of tumor responsive    Tlymphocyte cell lines for adoptive cancer immunotherapy. •  investigation of the contribution of immunological mechanisms    to the etiology of autism. For more information about these projects and other activities in the PonzioLab, visit our website at: http://www.umdnj.edu/~ponzio

Current Research

Cancer Immunotherapy With T Lymphocyte Cell Lines We are studying B cell lymphomas that arise spontaneously in several strains of mice, including SJL and C57L as prototypic models for cancer immunotherapy. These murine germinal center Derived B cell lymphomas exhibit dependence for their growth on cytokines produced by tumor-Activated CD4 + T helper (TH) lymphocytes, a phenomenon we have termed “reverse immune surveillance”.

The lymphoma cells express a tumor antigen that activates TH2 cells to produce cytokines, such as IL-4 and IL-5 that promote tumor growth. However, we are using other cytokines, such as IL-12, to change the T cell response to a TH1 rather than TH2 pattern. TH1 cells produce a different pattern of cytokines, including Interferon- g , which results in the development of tumor-specific Cytotoxic T Lymphocytes (CTL) that destroy tumor cells and prevent B lymphoma growth. We have developed tumor responsive TH1 cell clones that enhance the ability of naïve lymphocytes to become CTL. After injection of these TH1 cells, SJL mice are able to resist challenge with viable tumor cells. More importantly, TH1 cell-injected mice fail to develop the characteristic primary lymphomas that arise spontaneously at one year of age in 90% of uninjected SJL mice.

This novel form of adoptive cellular immunotherapy shows promise for development of similar strategies that can be used for treatment of cancer patients. Current areas of emphasis in this cancer model involve:

•  transfecting the TH1 cell clones with a permanent fluorescent marker to track their migration, localization and interaction with tumor cells in vivo .
•  development of tumor antigen-specific Cytotoxic T Lymphocyte (CTL) clones that can be used for adoptive immunotherapy
•  use of tumor specific CTL clones lines to identify, characterize and isolate tumor antigens that can be used for immunization to prevent tumor development

Immunological Mechanisms in Autism

Children with certain autism spectrum disorders exhibit an increase in restricted, repetitive stereotypical motor activity and immunological abnormalities, in addition to social and communicative deficits. Although the underlying causes of autism are not known, there is evidence that an autoimmune process that occurs early in life may contribute, in part, to the neurodevelopmental manifestations observed in children with autism. Additionally, there is evidence that products of an activated immune system (either endogenously produced or in response to environmental stimuli, such as infectious agents) are associated with autistic behavior.

Activation of certain components of the immune system (such as T helper lymphocytes) has been shown to influence development of those regions of the brain that mediate the behavioral abnormalities seen in autistic individuals. Cytokines, such as Interleukin-2 (IL-2), produced by activated T helper (TH) lymphocytes have also been implicated in the etiology of neurological disorders that involve stereotypical motor abnormalities, including autism. Using a mouse model for autism, we are investigating the ability of TH cell subpopulations to influence stereotypical motor behavior. TH cells are broadly divided into TH1 and TH2 subsets, each of which secretes a distinctive cytokine pattern following activation with antigen. TH1 cells secrete primarily IL-2 and Interferon- g , whereas TH2 cells produce IL-4, IL-5, and IL-10. Given the known ability of IL-2 to cause behavioral abnormalities, it is likely that TH1 cells mediate these effects.

The overall goal of our investigation is to determine if antigen-activated TH1 cells (and the cytokines they produce) can cause alterations of stereotypical motor behavior and immunocompetence that are characteristic of certain autism spectrum disorders. This study has significant clinical relevance for understanding the contributions of immunological mechanisms to the etiology and pathology in autism. Such basic scientific knowledge, which can only be obtained using experimental models, is the necessary first step in the development of therapeutic strategies that target the cause(s) of autism spectrum disorders.

Representative Publications

Erianne, G., Wajchman, J., Yauch, R., Tsiagbe, V.K., Kim, B.S., and Ponzio, N.M. B cell

lymphomas of C57L/J mice; the role of Natural Killer cells and T helper cells in lymphoma development and growth. Leukemia Research. 24:705-718, 2000.

Ponzio, N.M., and Thorbecke, G.J. Requirement for reverse immune surveillance for the growth of germinal center derived murine lymphomas. In: Reverse Immune Surveillance: An adaptive mechanism used by tumor cells to facilitate their survival and growth. (GJ Thorbecke and NM Ponzio, eds.) Seminars in Cancer Biology. 10:331-340, 2000

Sen, N., Simmons, W.J., Thomas, R.M, Erianne, G., Zhang, D.J., Jaeggli, N.S., Huang, C., Xiong, X., Tsiagbe V.K., Ponzio N.M, and Thorbecke G.J. META-controlled, env-initiated transcripts encoding superantigens of murine Mtv29 and Mtv7 and their possible role in germinal center B cell lymphomagenesis. J Immunology. 166:5422-5429, 2001.

Chong, S.Y., Zhang, M., Lin, Y-C., Coffman, F., Garcia, Z., Ponzio, N.M., and Ravechè, E. The growth regulatory role of B-cell-specific-activator-protein (BSAP) in NZB malignant B-1 cells. Cancer Immunology and Immunotherapy. 50:41-50, 2001.

Wajchman, J., Simmons, W.J., Klein, A., Koneru, M., and Ponzio, N.M. Interleukin-12-induced cytotoxicity against syngeneic B cell lymphomas of SJL/J mice. Leukemia Research. 26:577-590, 2002.

Natelson, B..H, Haghighi, M.H., and Ponzio, N.M. A review of the evidence on the presence of immune dysfunction in chronic fatigue syndrome.  Clinical and Diagnostic Laboratory Immunology. 9:747-752, 2002.

Chen,K., Shiflett, S.C., Ponzio, N.M., He, B., Elliott, B.S., and Keller, S.E. A preliminary study of the effect of external Qigong on lymphoma growth in mice. J Alternative and Complementary Medicine. 8:615-621, 2002.

Potian, J.A., Aviv, H., Ponzio, N.M., Harrison, J.S., and Rameshwar, P. Veto-like activity of mesenchymal stem cells (MSC): Functional discrimination between cellular responses to alloantigens and recall antigens. J Immunology. 171:3426-3434, 2003.

Simmons, W.J., Koneru, M., Mohindru, M., Thomas, R., Cutro, S., Singh, P., DeKruyff, R.H., Inghirami G., Coyle, A., Kim, B.S., Ponzio, N.M. Tim-3+ T-bet+ Tumor-specific TH1 cells co-localize with and inhibit development and growth of murine neoplasms. (Submitted for publication)