Role of Tissue-Resident Leukocytes in the Kidney – Implications for Allograft Survival According to Age

• Applicant: Professorin Dr. Katja Kotsch, Ph.D.
• Subject Area: General and Visceral Surgery ; Reproductive Medicine, Urology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421576852

Throughout the world, the number of individuals aged 60 years and older will increase to from 12% to approximately 22% of the population by 2050. Both, this demographic development together with the overall lack of suitable donor organs result in the increased usage of so-called expanded criteria donor organs (ECD). As these organs illustrate restricted allograft survival, it is of general importance to understand the underlying immunological mechanisms of rejection in order to improve the long term survival of senescent organs by therapeutic interventions. We already demonstrated that the identification of the biomarker NKG2D, an activating receptor, in biopsies is predictive for the outcome of senescent kidneys. In addition, we showed that the peri-operative conditioning of kidneys with the polyclonal antibody anti-lymphocyte globulin results in an improved graft function. In principle, the hallmark of a senescent immune system is characterized by a decline of naïve T cells parallel with an increase of clonally expanded effector/memory T cells. However, it has been demonstrated recently, that the majority of CD8+ memory T cells is not present in the periphery but reside in the intestine, lung and skin where they contribute to a local protective immune response by the rapid generation of effector molecules. It is not clarified yet, how this pool of long-living and tissue-resident T cells is modified during ageing and how it contributes to the rejection of solid organs such as kidney, the most frequent transplanted organ worldwide. Our preliminary data in an allogeneic murine kidney transplantation model illustrate, that recipient-derived T cells migrate into the organ shortly after transplantation, acquiring a tissue resident phenotype characterized by the expression of the integrin CD103 and the tissue retention marker CD69. By analysing resected human kidneys, we additionally demonstrate that endogenous, tissue-resident CD103+CD69+ T cells can be identified. Moreover, these cells derived from aged kidneys illustrate a CD28null phenotype, which is associated with a higher inflammatory potential. The aims of the study are therefore, under the special consideration of the risk factor age, to (i) characterize endogenous tissue-resident memory T cells in the kidney, to (ii) analyse their inflammatory potential, antigen specificity, clonality and metabolism, to (iii) examine the generation of tissue-resident memory in the allograft and to (iv) modulate or deplete these cells in order to prolong allograft survival.

• DFG Programme: Research Grants
• Co-Investigator: Privatdozent Dr. Frank Friedersdorff