Open Research Projects

Deciphering the role of macrophages for allograft quality and survival

Prinicipal Investigator

Prof. Dr. Katja Kotsch
Dr. Arne Sattler
Dr. Efstathios Stamatiades

Scientific interest within the context of the graduate college:

Our group is studying immune-mediated mechanisms of solid organ allograft rejection. Worldwide, the number of available donor organs is decreasing. Moreover, due to demographic changes in modern societies, the number of individuals with an advanced age >65 years is steadily increasing. This results in a higher number of patients diagnosed with progressive chronic kidney disease (CKD) constituting a potential kidney transplant recipient group. Accordingly, chronological donor age is also a major risk factor for allograft dysfunction, as grafts from older donors are more susceptible to ischemic injury and prone to restricted allograft outcome. Despite modern immunosuppressants, overall long-term survival of solid allografts is limited. The infiltration and activation of immune cells is one of the key mechanisms for chronic allograft failure, but the detailed molecular and cellular mechanisms underlying the complex interplay between donor and recipient – finally resulting in the rejection of the graft – are still not understood. Consequently, a better understanding of both, donor organ quality and allograft rejection is mandatory in order to overcome the current limitations of insufficient numbers of donor organs – and restricted allograft survival in the long term.

Project description:

Graft-infiltrating monocyte-derived macroprohages (mdMΦs) post transplantation are phenotypically indistinguishable from kidney-resident macrophages (krMΦs) hampering their discrimination in the graft. In order to explore the important role of krMΦs in graft survival, particularly in terms of donor-related risk factors (e.g. donor age, obesity), we will use state-of-the-art techniques including experimental transplantation models, genetic-fate-mapping, single-cell RNAseq and confocal/intravital/light-sheet microscopy to decipher renal macrophage biology in steady-state and renal transplantation. Experimental animal studies will be complemented by a comprehensive analysis of monocytes/macrophages from patient tissues (resected materials). This project will be embedded in the 2nd funding period of the SFB 1365 (Nephroprotection) at the Charité.

Application details

References

  1. Moreau A, Varey E, Anegon I, Cuturi MC. Effector mechanisms of rejection. Cold Spring Harb Perspect Med. 2013; 3(11):a015461. doi: 10.1101/cshperspect.a015461.
  2. Dornieden T, Sattler A, Pascual Reguant A, […], Boral S, Friedersdorff F, Kotsch K. Signatures and Specificity of Tissue-resident Lymphocytes Identified in Human Renal Peri-tumor and Tumor Tissue. J Am Soc Nephrol. 2021; 32:2223. doi: 10.1681/ASN.2020101528.
  3. Günther J, Resch T, Hackl H, […], Pascher A, Pratschke J, Kotsch K. Identification of the activating cytotoxicity receptor NKG2D as a senescence marker in zero-hour kidney biopsies is indicative for clinical outcome. Kidney Int. 2017; 91:1447-1463. doi: 10.1016/j.kint.2016.12.018.
  4. Stamatiades EG, Tremblay ME, Bohm M, […], Diebold S, Nimmerjahn F, Geissmann F. Immune Monitoring of Trans-endothelial Transport by Kidney-Resident Macrophages. Cell. 2016; 166:991-1003. doi: 10.1016/j.cell.2016.06.058.
  5. Carlin LM*, Stamatiades EG*, Auffray C, […], Cook HT, Diebold S, Geissmann F. Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal. Cell. 2013; 153:362-375. doi: 10.1016/j.cell.2013.03.010. *equal contribution.