1. Vaccine development against helminth infections.

Nematode-parasites of humans infect an enormous number of people in regions associated with poverty and poor living conditions and cause a wide range of diseases. The goals of this research project are: (1) to determine the mechanisms used by the immune response to kill these parasites and (2) to utilize the information gained on how the parasites are killed to develop vaccines against these infections. Two different nematodes are currently under study, Onchocerca volvulus, and Strongyloides stercoralis. O. volvulus is a filarial worm and is the causative agent of river-blindness and severe dermatitis in Africa and South America. S. stercoralis, an intestinal dwelling nematode, is found all over the world and causes chronic gastrointestinal disease in normal patients and fatal disease in immunosuppressed individuals. The questions addressed in the studies focused on the mechanism of protective immunity include: (1) What is the optimal method for immunizing animals against the infections? (2) How is the immune response to these parasites regulated? Specifically, what is the role of CD4 and CD8 cells, what is the role of Th1 and Th2 cells and what is the role of the cytokines produced by these cells? (3) What are the mechanisms that the immune response uses to kill the parasites in immunized hosts? What is the role of antibody with particular emphasis on the isotype of the essential antibodies and the molecules recognized by these antibodies? How do effector cells, including eosinophils and neutrophils, participate in the protective immune response. The second component of this study is the development of clinically applicable vaccines. Recombinant antigens have been identified and cloned based on their recognition by elements of the immune response. These antigens are then tested using different delivery systems to determine vaccine efficacy. Several recombinant antigens have been identified which were successful at inducing protective immunity to both infections in mice. Efforts are now directed to determine the optimal way to administer these antigens to induce immune resistance to the infections. 

2. Function of eosinophils in the control of helminth infections.

Eosinophils have been shown to be associated with the development of allergic responses and the control of helminth infections. The goal of this project is to determine the role of eosinophils in the innate and adaptive immune response of mice to the nematode parasite S. stercoralis. In previous studies we have shown that protective immunity to this parasite is dependent on IL-5 and on eosinophils. The specific goals of this project are: (1) To determine the role of eosinophils in killing larval S. stercoralis by the innate immune response. The approach taken is to determine if killing of larval S. stercoralis by the innate immune response is dependent on granule release from the eosinophils in the immediate environment of the larvae and which specific mouse eosinophil granule products are capable of killing larvae in vitro and in vivo. (2) To determine the role of eosinophils in the induction of the adaptive immune response to larval S. stercoralis. Previous studies have shown that eosinophils are essential for the induction of the adaptive immune response against S. stercoralis. Three roles for eosinophils in the induction of the immune response have been hypothesized, cytotoxic cells capable of killing and lysing the larvae, antigen presenting cells and cytokine producing cells. Experiments are in progress to determine if any or all of these hypotheses are correct. (3) To determine the role of eosinophils in killing parasites through the adaptive immune response. In this section we are studying how eosinophils participate in killing larvae in collaboration with IgM and complement.

Keywords:  parasite, eosinophil, immunology

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12. Krolewiecki, A.J., S. Leon, P.A. Scott, T. J. Nolan, G. A. Schad and D. ABRAHAM. 2001. Effect of chronic ethanol consumption on protective T-helper 1 and T-helper 2 immune responses against the parasites Leishmania major and Strongyloides stercoralis in mice. Alcoholism: Clinical and Experimental Research. 25:571-578.