Recruitment, activation and effector pathways of basophils in chronic allograft remodeling

• Applicant: Professor Dr. Matthias Mack
• Subject Area: Cardiology, Angiology ; Immunology
• Term: from 2019 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409355366

Heart transplantation is for many patients the best treatment for terminal heart failure. Acute transplant rejections can efficiently be prevented by immunosuppressive drugs, like calcineurin inhibitors. Chronic rejections however, occurring within months or years after transplantation, are rather resistant to therapy. These are characterized by vasculopathy, interstitial fibrosis and myocardial dysfunction. The mechanisms how transplant fibrosis develops are largely unknown. In previous studies we could show that basophils infiltrate the allografts and importantly contribute to fibrotic remodeling of transplanted hearts. Depletion of basophils and the use of IL-4 deficient recipients or IL-4R-deficient grafts revealed that basophils induce fibrosis and vasculopathy by the release of IL-4. However, it is still unclear how basophils are recruited into the transplants, how they are activated (upstream pathways) and how basophils and IL-4 induce fibrotic remodeling of allografts (downstream pathways). We would like to answer both questions and to also analyze the role of basophils in a newly established model of transplant fibrosis that is based on the withdrawal of cyclosporin A. In addition, we would like to analyze in patients whether basophils are present in chronically rejected transplants and whether they are also recruited during acute rejections.

• DFG Programme: Research Grants