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P-2.37 IL-21 as a new target for immunosuppressive therapies

Carla C. Baan, Netherlands

Head of laboratory
Internal Medicine
Erasmus MC, University, Medical Center

Biography


Carla C. Baan, PhD, is Professor and head of the Nephrology & Transplantation Laboratory at Erasmus Medical Center, University Hospital Rotterdam, The Netherlands. Dr Baan obtained her doctorate from Erasmus University, The Netherlands.
Her position involves the supervision of doctorate research related to the role of cytokines, regulatory T cells, B cells, cell therapy and immunosuppressive drugs in clinical organ transplantation.At the laboratory immunological tests to monitor pathways of donor directed reactivity are developed and used including multi-parameter flow cytometry/Facs sort and Elispot for T and B cell profiling, phosphospecific flow cytometry for the analysis of intracellular signaling pathways, cell culture assays to measure antigen specific proliferation & cytotoxicity, GWAS and PCR for gene expression and epigenetics, and immunohistochemistry.The aim of this translational work is to titrate the immunosuppressive burden on our patients in such a way that side-effects (infections, malignancies, cardiovascular events) are kept at a minimum while at the same time rejection processes are prevented.
Dr Baan has been the President of the European Society for Organ Transplantation (2011-2013) and has been a member of the board of the International Society for Heart and Lung Transplantation (2015-2016). Currently, dr Baan is the Executive Editor_Basic Sciences of the Transplantation Journal.

Recommended Reading Websites

Rotterdam Transplant Lab

Abstract

IL-21 as a new target for immunosuppressive therapies

Carla C. Baan1.

1Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands

Background: IL-21 is a T cell growth factor for and secreted by Th17 and T follicular helper (Tfh)-cells. This cytokine has a diverse effect on a broad range of immune cells. It regulates CD8+ T cell expansion and their effector functions, and is crucial for T cell-dependent B cell differentiation of antigen-activated B cells into antibody-producing plasma cells.  However, little is known about IL-21 mediated T and B cell responses in alloreactivity after organ transplantation.
Materials and Methods: First, we explored the actions of IL-21 in alloreactive T cell proliferation and cytotoxicity in mixed lymphocyte reactions. Second, to test the role of IL-21 producing Tfh cells in the regulation of B cells in an alloantigen-driven setting, we performed co-culture experiments of kidney transplant patient Tfh cells and B cells that were stimulated with donor antigen. Third, the effect of an aIL-21R blocking antibody on the early phase of allograft rejection was studied in a humanized skin transplantation model in mice reconstituted with human T and B cells.
Results: Alloactivated T and B cells highly express IL-21R. In the presence of IL-21, a marked increased proliferative response of alloactivated T cells was found. Also, the expanded CD8+ T cells had significant cytolytic functions, while blockade of the IL-21 route by an aIL-21R antagonist inhibited the proliferation of alloactivated T-cells. Next, we determined the role of IL-21 in T cell dependent B cell responses. Donor antigen stimulation of the co-cultured Tfh – B cells initiated expression of the activation markers ICOS and PD-1 on Tfh cells with a shift toward a mixed Tfh2 and Tfh17 phenotype. The alloantigen activated memory B cells underwent class switch recombination and differentiated toward IgM- and IgG-producing plasmablasts. Anti-IL-21R antagonists significantly inhibited B cell differentiation. Finally, in the humanized mouse skin transplant model, in mice treated with the aIL-21R antagonist reduced signs of alloreactivity were measured including significantly less CD4+ and CD8+ T and B cell infiltration and less expression of inflammatory markers Keratin 17 and Ki67.
Conclusion: These data show that comparing the effects of new IL-21-targeting therapeutics against the conventional immunosuppressants used in transplantation would be of considerable interest. Blockade of the IL-21 pathway may provide a new perspective for the treatment of T and B cell mediated allogeneic responses after organ transplantation.

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