Organ Transplantation|Prof. Dr. Edward Geissler

Background

The research group of Prof. Geissler is engaged in Transplantation Immunology research, with one aim being the development of strategies to reduce organ transplant rejection and reduce the need for conventional immunosuppressive drugs. To this end, he is presently leading a recently established EU-FP7 international consortium (The ONE Study) aimed at applying immunomodulatory cellular therapy to renal transplant recipients as a means of reducing allograft rejection. Prof. Geissler also coordinates a DFG funded Clinical Research Group (KFO 243) aimed at studying the early immunological determinants of late transplant outcome; new treatment strategies for reducing transplant-related pathology are expected to be clinically translated from this research.

Associated with the RCI, Prof. Geissler and Dr. James Hutchinson concentrate on the study of a regulatory macrophage population that has promising therapeutic potential in humans; two renal transplant recipients have already been treated with these cells (J Immunol, 187:2072-2078, 2011). Regulatory macrophages will be used by this group for promoting kidney allograft acceptance in The ONE Study. However, much remains unknown about how regulatory macrophages function to promote tolerance to allografts. The group will as part of the RCI initiative test the following:

Scientific Objectives

  • Objective 1: To establish GMP-compliant, serum-free tissue culture conditions for manufacturing M regs.
  • Objective 2: To identify a naturally-occurring counterpart of the ex vivo-generated human M reg in tissues.
  • Objective 3: To study the effect of M reg on co-cultured T cell and dendritic cell populations.
  • Objective4: To contribute to the establishment of an integrated immune monitoring facility.

Work programme

Objective 1:

An accurate specification of the human M reg has been defined, both in terms of marker phenotype and in vitro functions. At least four components of human serum (one of which is aggregated Ig) are necessary for the development of M regs from human peripheral blood monocytes. Using various biochemical techniques, we have narrowed-down the search for the other three factors to two proteins and a chloroform-soluble factor, which may be a fatty acid. Once identified, these factors could be used to support the production of human M regs for clinical purposes under serum-free culture conditions.

Objective 2:

Ethics Committee approval for a clinical study in which M reg-like macrophages will be identified in human spleen has been granted. The group intends to isolate splenic M reg-like cells using magnetic beads and flow cytometry sorting in order to test their phenotype and functions.

Objective 3:

The overarching aim of this aim is to ascertain whether M regs can induce T cell-mediated regulatory responses through a direct interaction of M regs and T cells, and to provide a mechanistic account of this interaction. In addition, the effect of M regs on dendritic cell phenotype will be examined, with the hypothesis that M reg alter dendritic cell function, which in-turn suppress the immune response through multiple mechanisms.

Objective 4:

Monitoring of immunological parameters in patients undergoing experimental immunotherapies is of increasing importance, in order to prove a pharmacodynamic effect and to evaluate treatment efficacy. This research group has established clinical pathways, lab facilities and immune monitoring techniques to perform serial analyses on patients undergoing solid organ transplantation. The results from this immune monitoring effort are being used to define secondary end-points in clinical studies aimed at promoting allograft acceptance, including the MiSOT-I Study and The ONE Study. There is significant overlap between immune monitoring activities undertaken in Surgery and other departments; therefore, combining the expertise of these groups within the RCI is eminently sensible.

Publications

  • Chapman JR, Baan CC, Bromberg JS, Geissler EK, Pomfret EA, Tullius SG. (2017) Highlights in Clinical Science. Transplantation. 101(6): 1121–1124.
  • Riquelme PAmodio G, Macedo C, Moreau A, Obermajer N, Brochhausen C, Ahrens N, Kekarainen T, Fändrich F, Cuturi C, Gregori SMetes DSchlitt HJThomson AWGeissler EKHutchinson JA. DHRS9 is a stable marker of human regulatory macrophages. Transplantation.2017 Jun 7 (Epub ahead of print).
  • Hutchinson JAAhrens NGeissler EK. MITAP-compliant characterization of human regulatory macrophages. Transpl Int2017 May 20 (Epub ahead of print).
  • Geissler EK. (2017) Consortium ONE Study: Immunotherapy after kidney transplantation. Le Courrier de la Transplantation. Vol. XVII - No. 2, 77-78.
  • Ribechini E, Hutchinson JA, Hergovits S, Heuer M, Lucas J, Schleicher U, Jordán Garrote AL, Potter SJ, Riquelme P, Brackmann H, Müller N, Raifer H, Berberich I, Huber M, Beilhack A, Lohoff M, Bogdan C, Eyrich M, Hermanns HM, Geissler EK and Lutz MB. (2017) Novel GM-CSF signals via IFN-γR/IRF-1 and AKT/mTOR license monocytes for suppressor function. Blood Advances. 1:947-960.
  • Hutchinson JARiquelme PBach CKekarainen TFändrich FGeissler EKAhrens N. (2017) Donor-specific anti-HLA antibodies present in pooled human serum do not prevent development of human Mreg_UKR from monocytes in culture. Transplantation. 101(5)e188-e190.
  • Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, Kastenberger M, Bogdan C, Schleicher U, Mackensen A, Ullrich E, Fichtner-Feigl S, Kesselring R, Mack M, Ritter U, Schmid M, Blank C, Dettmer K, Oefner PJ, Hoffmann P, Walenta S, Geissler EK, Pouyssegur J, Villunger A, Steven A, Seliger B, Schreml S, Haferkamp S, Kohl E, Karrer S, Berneburg M, Herr W, Mueller-Klieser W, Renner K, Kreutz M. (2016) LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells Cell Metab. 24(5):657-671.
  • Lord P, Spiering R, Aguillon JC, Anderson AE, Appel S, Benitez-Ribas D, Ten Brinke A, Broere F, Cools N, Cuturi MC, Diboll J, Geissler EK, Giannoukakis N, Gregori S, van Ham SM, Lattimer S, Marshall L, Harry RA, Hutchinson JA, Isaacs JD, Joosten I, van Kooten C, Lopez Diaz de Cerio A, Nikolic T, Oral HB, Sofronic-Milosavljevic L, Ritter T, Riquelme P, Thomson AW, Trucco M, Vives-Pi M, Martinez-Caceres EM, Hilkens CM. (2016) Minimum information about tolerogenic antigen-presenting cells (MITAP): a first step towards reproducibility and standardization of cellular therapies. PeerJ. 4:e230.
  • Haarer J, Riquelme P, Hoffmann P, Schnitzbauer A, Schlitt HJ, Sawitzki B, Geissler EK, Hutchinson JA. (2016) Early enrichment and restitution of the peripheral blood Treg pool is associated with rejection-free stable immunosuppression after liver transplantation. Transplantation. 100(7):e39-40.
  • Hutchinson RWMcLachlin KMRiquelme PHaarer JBroichhausen CRitter U,  Geissler EKHutchinson JA. (2015) Laser Ablation Inductively Coupled Plasma Mass Spectrometry: An Emerging Technology for Multiparametric Analysis of Tissue Antigens Transplant Direct.1(8):e32.
  • Soeder Y, Loss M, Johnson CL, Hutchinson JA, Haarer J, Ahrens N, Offner R, Deans RJ, Van Bokkelen G, Geissler EK, Schlitt HJ, Dahlke MH. (2015) First-in-human case study: Multipotent adult progenitor cells for immunomodulation after liver transplantation. Stem Cells Transl Med. 4:899-904.
  • Geissler EK, Hutchinson JA. (2013) Cell therapy as a strategy to minimize maintenance immunosuppression in solid organ transplant recipients. Curr Opin Organ Transplant 18:408.
  • Riquelme P, Geissler EK, Hutchinson JA. (2012) Alternative approaches to myeloid suppressor cell therapy in transplantation: comparing regulatory macrophages to tolerogenic DCs and MDSCs. Transplant Res 1:17.
  • Riquelme P, Tomiuk S, Kammler A, Fändrich F, Schlitt HJ, Geissler EK, Hutchinson JA.  IFN-γ-induced iNOS expression in mouse regulatory macrophages prolongs allograft survival in fully immunocompetent recipients. Mol Ther 21:409.
  • Hutchinson JA, Riquelme P, Geissler EK. (2012) Human regulatory macrophages as a cell-based medicinal product. Curr Opin Organ Transplant. 17:48.
  • Hutchinson JA, Riquelme P, Sawitzki B, Tomiuk S, Miqueu P, Zuhayra M, Oberg HH, Pascher A, Lützen A, Janßen U, Broichhausen C, Renders L, Thaiss F, Scheuermann E,  Henze E, Volk HD, Chatenoud L, Lechler RI, Wood KJ, Kabelitz D, Schlitt HJ, Geissler EK, Fändrich F. (2011) Cutting Edge: Immunological Consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol. 187:2072.
Maps