Dr. Adam Griesemer's Research
The Griesemer Laboratory utilizes translational models to investigate the ability of mixed chimerism to induce tolerance across allogeneic and xenogeneic barriers.
My laboratory is investigating the ability of ex-vivo expanded Tregs to enhance bone marrow engraftment and extend the duration of mixed chimerism. The induction of durable mixed chimerism without graft-versus-host disease should in turn lead to life-long donor-specific tolerance to any co-transplanted cells (islets) or solid organs (heart, liver, lung) from the donor. We are also collaborating with other investigators at the CCTI to study the ability of amnion-derived multipotent progenitor cells to enhance bone marrow engraftment in translational models as an alternate, and potentially synergistic, strategy to induce durable mixed chimerism.
We are also investigating the ability to translate the induction protocol that induces tolerance to simultaneously co-transplanted bone marrow and kidney grafts (despite only transient mixed chimerism developing) to combined bone marrow and liver grafts. In particular, we are investigating 1) the role of donor and recipient memory cells in mediating host-versus-graft and graft-versus-host responses; and 2) the role that inflammatory cytokines, particularly in the portal system, play in priming inflammatory and tolerogenic cellular responses.
The future goals of the laboratory include collaborating with the Chen lab in testing the ability of durable mixed chimerism to induce tolerance to organs that do not facilitate tolerance with the transient mixed chimerism approach, such as islets. We also plan to test the ability of modulating the T cell memory responses and the inflammatory environment induced after liver transplant to reliably induce rapid tolerance after liver transplants.
The development of Gal-knockout swine removed the most significant target of natural antibodies from the surface of pig cells. However, low levels of non-Gal antibodies represent a barrier to long-term solid organ xenograft survival and xenogeneic bone marrow engraftment. Since pharmacological interventions have been unsuccessful in decreasing natural antibody levels, my lab is investigating the efficacy of Treg therapy in reducing anti-swine antibodies and facilitating tolerance induction to xenotransplants.
Current investigations include:
• Studies on the optimal method of stimulating Tregs during expansion to generate donor-specific Tregs
• Suppression of xenogeneic natural antibodies by donor-specific Tregs in preclinical models
• Augmentation of xenogeneic chimerism using donor-specific Tregs
The future goals of the laboratory are to utilize donor-specific Tregs to control the natural anti-swine antibody response in translational swine-to-humanized mice and swine-to-nonhuman primate models. This in turn will facilitate the induction of xenogeneic chimerism that is expected to result in robust tolerance to donor solid organ transplants.
Current Lab Members:
Paula Alonso-Gaullart, DVM
Sulemon Chaudry, MD
Jeffery Stern, MD
Previous Lab Members:
Joshua Weiner, MD
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Weiner J, Duran-Struuck R, Zitsman J, Buhler L, Sondermeijer H, et al. Restimulation After Cryopreservation and Thawing Preserves the Phenotype and Function of Expanded Baboon Regulatory T Cells. Transplantation Direct. 2015 February; 1(1):1-7.
Griesemer A, Yamada K, Sykes M. Xenotransplantation: immunological hurdles and progress toward tolerance. Immunol Rev. 2014 Mar;258(1):241-58. PubMed PMID: 24517437; PubMed Central PMCID: PMC4023346.
Griesemer A, Liang F, Hirakata A, Hirsh E, Lo D, Okumi M, Sykes M, Yamada K, Huang CA, Sachs DH. Occurrence of specific humoral non-responsiveness to swine antigens following administration of GalT-KO bone marrow to baboons. Xenotransplantation. 2010 Jul;17(4):300-12. PMID: 20723202
Griesemer A, Hirakata A, Shimizu A, Moran A, Tena A, Iwaki H, Ishikawa Y, Schule P, Arn J, Robson S, Fishman J, Sykes M, Sachs D, Yamada K. Results of Gal-Knockout porcine thymokidney xenografts. Am J Transplant. 2009 Dec;9(12):2669-78. PMID: 19845583
Griesemer A, Yamada K, and Sachs DH. “Strategies for Immune Tolerance Induction in Islet Transplantation and Xenotransplantation” Chapter in Islets: Biology, Immunology, and Clinical Transplantation Dr. Fouad Kandeel, Editor, In Press. ISBN-10: 0387795774
Griesemer AD, Okumi M, Shimizu A, Moran S, Ishikawa Y, Iorio J, Arn JS, Yamada K. Upregulation of CD59: potential mechanism of accommodation in a large animal model. Transplantation. 2009 May 15;87(9):1308-17. PMID: 19424030
Griesemer AD, Lamattina JC, Okumi M, Etter JD, Shimizu A, Sachs DH, Yamada K. Linked suppression across an MHC-mismatched barrier in a miniature swine kidney transplantation model. Journal of Immunology. 2008 Sep 15;181(6):4027-36. PMID: 18768858
Griesemer AD, Sorenson EC, Hardy MA. The Role of the Thymus in Tolerance. Transplantation. 2010 Sep 15;90(5):465-74. PMID: 20555306
Yamada K, Griesemer A, Sykes M, Sachs DH. Cotransplantation of vascularized thymus and kidney from GalT-KO pigs to baboons. Xenotransplantation. 2007 Mar;14(2):186-9.
Wong BS, Yamada K, Okumi M, Weiner J, O'Malley PE, Tseng YL, Dor FJ, Cooper DK, Saidman SL, Griesemer A, Sachs DH. Allosensitization does not increase the risk of xenoreactivity to alpha1,3-galactosyltransferase gene-knockout miniature swine in patients on transplantation waiting lists. Transplantation. 2006 Aug 15;82(3):314-9. PMID: 16906027
Yamada K, Griesemer A, Okumi M. Pigs as xenogeneic donors. Transplantation Reviews, 2005 June, 19(3) pp. 164-177.