The General approach
The General approach
The group of Nathan Karin focuses on the role of different subtypes of T cells in regulating the interface between cancer and autoimmunity, in particular how small proteins secreted by immune cells named chemokines direct the biological properties of these cells. The basic pioneered approach developed in the lab long ago (Meiron et al J. Exp. Med. 2008) is based on successful stabilization of these short-lived proteins as stable Ig based fusion protein and to administer each of them during ongoing cancer and autoimmunity and learn how they affect the manifestation of each disease. Highly modern tools (single cell RNAseq, CyTOF etc.) are then applied to investigate the mechanistic basis of action.
The model of diseases
es in cancer diseases
Melanoma : also known as malignant melanoma, is a type of cancer that develops from the pigment-producing cells known as melanocytes. Of all can cancer disease it appears that in melanoma the immune system plays a major role in limiting the disease. The immunological basis of disease is also well established. Therefore, this disease and its experimental models are of a major interest for us.
Melanoma key model: Transgenic expression of the RET receptor tyrosine kinase (RET) proto-oncogene under control of the metallothio-nein (MT1) promoter gave rise to a melanoma model that resembled the human disease. We are using a transferred model in which RET pre line overexpressing a reporter gene (mCherry gene) that allows follow-up of micro-metastasis. The working hypothesis that we are exploring is that chemokines has a direct effect on tumor growth and indirect effect via shaping the tumor microenvironment. We are exploring both possibilities, in part by using chimeric mice lacking specific chemokine receptors, while expressing these receptors on tumor cells.
Current major focus Exploring the role of CXCR3 and two of its ligands CXCL9 and CXCL10 in cancer
Multiple Sclerosis (MS)
MS key model: Experimental autoimmune encephalomyelitis (EAE) is a T cell mediated autoimmune disease of the central nervous system (CNS). Of all autoimmune disease models, the mouse EAE model is the most defined (immunologically) model of an autoimmune disease, including the ability to develop disease specific T cell lines and use them for in vivo research. The lab uses this model to elucidate key questions in immunological tolerance and its breakdown in autoimmunity.
Exploring the biological basis of self- non-self recognition by the immune system
Exploring the biological basis of self- non-self recognition by the immune system, in particular how immunological tolerance is actively maintained in Multiple Sclerosis, type I diabetes and Intestinal Bowel’s disease (IBD) .
Current major focus
Exploring the differential role of two different types of regulatory T cells in the regulation of disease: those that do not express FOXp3 and are also known as Tr1 cells, and those expressing FOXp3 (FOXp3+ T regs). As for FOXp3+ Tregs are studying the mechanism by which specific subtype of these cells that are CCR8+ operate via CCL1. As for Tr1 we are working on a novel mechanism by which signaling via scavenger receptors may induce their activities to restrain autoimmunity. Our lead model is EAE.