GENERATION OF A TRANSGENIC FCRI-KO/ HIGH IGE-PRODUCER MOUSE TO ELUCIDATE THE ROLE OF IGE IN TUMOR SURVEILLANCE

Immunoglobulin E (IgE) is a powerful elicitor of anti-parasitic immunity and play a key role in pathophysiology of allergic reactions.IgE antibodies acts by engaging both high and low affinity receptors, FcεRI and CD23. Since the 1960s a number of epidemiological studies have investigated the potential association between a history of allergy and risk of malignancy. In this direction studies were planned by redirecting the power of the IgE system towards tumors, and to evaluate if it can trigger powerful anti-tumor cytotoxic activities. Previously in our laboratory,mouse and human IgE have been used as vaccines adjuvants,highlighting the importance of IgE:FcεRI interaction in establishment of strong allergy-like inflammatory response at tumor site,with induction of adaptive antitumor immune response and memory. Based on these results and Epidemiological studies relating possible link between allergies and cancer protection, we decided to study the involvement of endogenousIgE with antitumor specific IgE effect in vivo making use of high IgE producing(KN1-HyperIgE) and IgE knock out transgenics and two different tumor cell lines (TS/A-LACK and N2C), upon challenge we were able to note that tumor growth was seen in IgE knock out mice, wild type control mice and CD-23 knock out mice, however there was a striking tumor protection effect in KN1-HyperIgE mice. The results from in vitro studies showed presence of tumor specific IgE antibodies in serum of only in KN1-high IgE producing group indicating the role of IgE mediated mechanism in antitumor protection. In order to prove the involvement of Endogenous IgE in antitumor protection observed in vivo, we investigated if Bone Marrow cells of KN1-HyperIgE producing mice when transplanted can induct protection in spontaneously tumor developing mice(HER-2/neuT),BMT experiments were performed using the bone marrow cells from HyperIgE mice failed to have delayed and/or desired antitumor effect in immunocompromised spontaneous tumor developing HER-2/neuT mice. To validate that indeed IgE is involved in tumor protection and this protection is mediated by its interaction with its high affinity receptor FcεRI, a new transgenic was generated by breeding KN1-HyperIgE and FcεRIα knock out mice to arrive at a Double mutant(DB) mice(phenotype being high IgE producing but lacking in functional high affinity receptor FcεRI). In experiment with tumor challenge, there was tumor protection in HyperIgE mice, but was lost in the double mutant mice inducting the role of high affinity receptor FcεRI in tumor protection. Even the in vitro results showed the release of antitumor specific IgE antibodies in KN1-high IgE producing as well as Double mutant group indicating that tumor protection lost in Double mutant mice is due to 5 absence of functional high affinity receptor FcεRI .In another experiment, depletion of CD8+ cells led to abolishment of tumor protection in Kn1-HyperIgE mice. The results from this thesis study clearly signify the role of IgE in antitumor mechanism and highlight the prominent role of IgE:FcεRI in induction of Tumor protection. It also points towards crucial role of CD8+cells in antitumor immunity, suggesting towards an IgE mediated cross presentation pathway for induction of TAA specific cytotoxic lymphocytes in antitumor response. Studies are ongoing to further elucidate the evolving role IgE mediated mechanism in the context of cancer.