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Selina Christen, Martin Holdener, Jessica Horn, Edith Hintermann, Monika Bayer and Urs Christen
In collaboration with Matthias G. von Herrath, La Jolla Institute for Allergy and Immunology, San Diego, California, USA
Trafficking of lymphocytes is orchestrated by various chemoattractant cytokines (chemokines) released upon external stimuli, such as virus-infection or tissue transplantation. We found that the CXCR3 chemokine ligand IP-10 (CXCL10) plays a central role in attracting autoaggressive cells to the target tissue in three scenarios:
(i) In a virus-induced model for T1D (RIP-LCMV mouse) pancreatic IP-10-expression was essential for the induction of diabetes by recruiting a critical mass of autoaggressive lymphocytes to the pancreas (Christen et al (2003) J. Immunol 171: 6838-6845).
(ii) In both RIP-LCMV and non-obese diabetic (NOD) mice, expression of IP-10 during the ongoing autoimmune destruction of the islets outside of the pancreas, induced by a virus that predominantly infects the pancreatic lymph nodes, draws autoaggressive cells out of the pancreas and abrogates T1D (Christen et al (2004) J. Clin. Invest. 113: 74-84).
(iii) Transgenic mice expressing IP-10 specifically in the b-cells (RIP-IP-10 mice) do not spontaneously develop T1D, but have enormous peri- and intra-islet infiltrations, indicating that antigen non-specific (bystander) activation is not sufficient to induce autoimmunity. However, b-cell specific expression of IP-10 massively accelerated T1D in the RIP-LCMV mouse (Rhode et al (2005) J. Immunol. 175: 3516-3524).
Hence, a non-specific inflammatory component of the innate immune system (IP-10) influences the development of antigen-specific autoimmunity depending on time and location of expression
A) Blockade of IP-10 (CXCL10) mediated cell migration with a small molecule CXCR3 antagonist
Selina Christen, Martin Holdener and Urs Christen
In collaboration with Hans-Günter Zerwes, Novartis, Basel, Switzerland
As an alternative to the use of neutralizing monoclonal antibodies to CXCL10 or CXCR3 we evaluated the small molecule CXCR3 antagonist NIBR2130 in a virus-induced mouse model for T1D. We found that the overall frequency of T1D was not reduced in mice administered with NIBR2130. An initial slight delay of diabetes onset was not stable over time since the mice turned diabetic upon removal of the antagonist. Accordingly, no significant differences in the islet infiltration rate and the frequency and activity of islet antigen-specific T cells between protected mice administered with NIBR2130 and control mice was found. Our data indicate that in contrast to direct inhibition of CXCL10, blockade of CXCR3 with the small molecule antagonist NIBR2130 has no impact on trafficking and/or activation of autoaggressive T cells and is not sufficient to prevent T1D.
Publication: Christen et al (2011) Clin Exp Immunol 165: 318-328
B) Role of RANTES (CCR5) in virus induced type 1 diabetes
Jessica Horn, Martin Holdener and Urs Christen
RANTES is a key chemokine in inflammation and prodominatly acts on macrophages and activated T-cells. Here we ask whether RANTES is necessary for the induction of autoimmunity in LCMV-infected RIP-LCMV mice in a similar way than IP-10. In contrast to IP-10, which is expressed very early and uniquely after LCMV-infection, RANTES is expressed at a later time when T-cells have already entered the pancreas and many other cytokines and chemokines are expressed as well (Christen et al (2003) J. Immunol 171: 6838-6845). Thus, RANTES might play a more important role in clearing LCMV (to prevent a chronic infection) rather than pushing the inflammation towards autoimmunity
Selina Christen, Edith Hintermann, Monika Bayer and Urs Christen
Here we further characterize the influence of IP-10 on the development of type 1 diabetes. We use the RIP-LCMV mouse model to investigate how an unspecific bystander inflammation can cause an antigen-specific, aggressive immune response that subsequently results in autoimmune disease. By combining a sub-diabetic dose of the b-cell toxin streptocotozin (STZ) with islet-specific overexpression of IP-10 in RIP-IP-10 x RIP-LCMV mice we want to push an non-specific inflammation towards autoimmunity.