The Research Laboratory of Nicholas Ponzio |
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Research Projects | Facilities
Research Projects
Areas of interest and ongoing research projects in the Ponzio laboratory related to cellular/molecular immunology and hematopoietic stem cell transplantation, including investigations of the:
- Cancer immunotherapy using tumor-specific T helper-1 cells for B cell lymphomas
- Contribution of immunological mechanisms to autism
- Hematopoietic Enhancing Effect by which HUCB cells exhibit a heretofore unrecognized ability to promote hematopoietic differentiation of bone marrow stem cells
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 a 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.
Cancer Immunotherapy Using Human Umbilical Cord Blood Cells: This investigation involves the use of Human Umbilical Cord Blood (HUCB) mononuclear cells for adoptive therapy using an in vivo animal model in which injected HUCB cells rescue mice from the lethal effects of high dose irradiation or chemotherapeutic drugs by stimulating endogenous hematopoiesis by the recipient's own progenitor cells. This property of HUCB cells was termed the Hematopoiesis Enhancing Effect (HEE), and is being used to facilitate engraftment of very low numbers of syngeneic and allogeneic T cell depleted BM cells in irradiated recipients. This provides a model to mimic clinical scenarios in which purified autologous hematopoietic stem cells are being used for transplantation as an adjunct to treatments in which irradiation or chemotherapeutic drugs are administered to patients. When allogeneic BM cells are used, it provides a model to investigate how the HEE of HUCB cells can be used to not only facilitate engraftment, but also to avoid the untoward side effects of Graft-versus-Host reactions in the recipient. Based on the results of these studies, UMDNJ has applied for a patent for this novel use of HUCB cells, which is currently under review by the United States Patent and Trademark Office.
Facilities
The Ponzio Lab has a large variety of equipment and resources necessary for conducting cutting edge immunological research. The lab consists of two biosafety laminar flow hoods for tissue culture, UV and light microscopes, a centrifuge and microfuge, a PCR machine, personal and departmental forma space, a scintillation counter, and a gamma counter. In addition to this equipment, the Ponzio Lab has access to numerous core facilities available school-wide. These include a Molecular Resource Facility, a Research Animal Facility, a Clinical Research Group, a Proteomics Facility, a Transgenic Mouse Facility, and a Confocal Microscopy Facility. For more information about school-wide research facilities, please visit the Office of Research and Sponsored Programs.