Dr. Raimon Duran-Struuck, DVM, PhD, Diplomate ACLAM, joined Penn as associate director of University Laboratory Animal Resources (ULAR) and assistant professor in the Pathobiology Department Division of Laboratory Animal Medicine. Raimon is a trained laboratory animal veterinarian and his research focuses on preventing graft rejection through development of therapies that increase immunological tolerance in recipients. As a comparative medicine veterinarian, Raimon aids scientific and clinical investigators with animal modeling, and works to develop (and refine) preclinical animal models that can translate with high fidelity to the clinic.
Dedicated to the improvement of human and animal health
Raimon received his veterinary degree from Tufts University School of Veterinary Medicine. Afterwards, he pursued a clinical and surgical internship at the Florida Veterinary Specialists and Cancer Treatment Center. Raimon’s strong interests in clinical immunology and transplantation led him to seek a four-year laboratory animal residency training program at the University of Michigan, where he joined the bone marrow transplant laboratories of Drs. Pavan Reddy and James Ferrara. During this time, Raimon was struck by the profound impact that graft vs. host disease (GVHD) has on pediatric patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT).
Enabled by a K01 award, Raimon developed large animal transplantation models capable of enhancing translation from cage- to bed-side at the Transplantation Biology Research Center, Massachusetts General Hospital and Harvard University, under renowned transplant researchers Dr. David H. Sachs, MD and Christene Huang PhD. Specifically, he focused on the development of a miniature swine large animal tumor model and the development of hematopoietic cell transplantation protocols to achieve mixed hematopoietic chimerism as a platform for generating immunological tolerance (see below).
During that time, Raimon also completed his PhD in Immunology (at the Universitat Autonoma de Barcelona) and was promoted to instructor in surgery at the Harvard Medical School and Assistant Immunologist at the Massachusetts General Hospital. In 2012, Raimon became an Assistant Professor in Surgical Sciences at the Columbia University Medical Center and Head of the Large Animal Pre-Clinical Transplant Laboratories. In collaboration with scientists and clinicians, he established a liver, kidney, bone marrow and pancreatic islet pre-clinical transplant program. Raimon came to Penn in late 2015 to join a well-respected laboratory animal medicine program and a top medical and veterinary research community to continue his exciting work, which he hopes can be translated to both human and veterinary patients. His current research focuses on cellular therapies exploiting the immunomodulatory roles of regulatory T cells and the use of genetically engineered cells for the treatment of rejection and autoimmunity in large animal models.
Immunological tolerance and why it is important in transplantation and autoimmunity
When a transplanted immunocompetent host recognizes a foreign (donor) graft, the consequent immune response can lead to graft rejection. The greater the degree of genetic disparity between donor and recipient, the more likely rejection is to occur. To control rejection, patients are required to take life-long immunosuppressive medications that are associated with infections and many comorbidities. Unfortunately, thousands of patients die worldwide waiting for a transplant because a suitable donor is never identified or because they are unable to withstand the toxic immunosuppressive protocols. Identifying protocols that promote immune tolerance to foreign grafts would greatly reduce this number by permitting the acceptance of genetically disparate grafts and avoiding the toxicity of immunosuppressants. Immune recognition of foreign molecules is primarily driven by T cell recognition of major histocompatibility complex (MHC)- peptide complexes.
While such recognition is beneficial for the control of a a myriad of foreign pathogens; unfortunately 10-20% of T cells can also recognize antigens derived from a donor graft, leading to graft rejection or graft-vs-host disease (GVHD) in alloHCT. In addition, a fraction of T cells can recognize self antigens. While central tolerance mechanisms eliminate the vast majority of self-reactive T cells, peripheral tolerance mechanisms are required to delete or functionally inactivate autoreactive T cells that have escaped.
The importance of regulatory T cells (Tregs) in preventing activation of autoreactive T cells is also demonstrated by increases in autoimmune diseases (such as Type I diabetes, etc) in the absence of Tregs. The Duran-Struuck laboratory is interested in manipulating central and peripheral tolerance mechanisms to develop novel approaches to “re-set” the immune system so that donor cells or organs are recognized as “self”, thereby reducing the chance of graft rejection and GVHD.
Mixed chimerism and regulatory T cell therapy for tolerance induction and prevention of graft-versus-host disease and rejection
Allo-HCT is a powerful therapy for the treatment of many malignant and non-malignant lymphohematopoietic disorders and is also important for the development of immunological tolerance for solid organ transplantation. Unfortunately, because donor T cells are introduced during this process, allo-HCT is often met with GVHD, a lethal side effect, whereby donor T cells attack all of the recipient’s tissues (mainly liver, gut, skin and the lymphohematopoietic organs). Dr. Duran-Struuck is interested in controlling GVHD (or rejection in the case of solid organ transplantation) by modulating allo-immune responses(1).
As outlined below, the laboratory works closely with investigators within the University of Pennsylvania Perelman School of Medicine and Penn Vet clinicians and scientists. Successful allo-HCT can establish a state of tolerance to tissues or organs from the same marrow donor due to the persistence of a small number of donor bone marrow-derived cells in the recipient, a state known as “mixed hematopoietic chimerism”.
Unfortunately, the ideal mixed chimeric state is often difficult to maintain and imbalance or activation of donor or host lymphocytes can lead to GVHD or graft loss. Dr. Duran-Struuck studies how this mixed chimeric state can be manipulated (and enhanced) in miniature swine by using donor leukocyte infusions (a cellular therapy used for cancer treatment) to maintain beneficial graft-versus-host responses without GVHD(2, 3).
In addition, the laboratory continues to focus on developing GVHDfree allo-HCT protocols across MHC barriers (where donor and recipient are genetically disparate). Recent work by Dr. DuranStruuck demonstrated that co-infusion of bone marrow plus Tregs (4) led to robust engraftment (of the donor marrow) and immunological tolerance. The new marrow graft was long-lived and GVHD was never induced. Moreover, tolerance was robust as a donor kidney transplanted months after the original BMT survived without use of immunosuppressants (4). Dr. Duran-Struuck currently aims to further refine cellular therapies by developing more efficient protocols for expanding polyclonal Tregs and engineering antigen specific Tregs (CAR Tregs) for treatment of solid organ rejection, GVHD and autoimmune disorders. Indeed, in a project funded by the Helmsley Foundation, Dr. Duran-Struuck, working in collaboration with Dr. Jim Riley and Ali Naji and lab teammates Gavin Ellis PhD and Delaine Wynn BS at Perelman School of Medicine, aim to design donor-specific CAR Tregs to protect donor pancreatic islets grafts for the treatment of Type-I diabetes.
Development of miniature swine as a large animal tumor model of cellular immunotherapies
The lack of a large animal transplantable tumor model has limited the study of novel therapeutic strategies for the treatment of liquid cancers. Swine provide a natural option based on their similarities to humans and their extensive use in biomedical research. Specifically, the Massachusetts General Hospital miniature swine herd retains unique genetic characteristics that facilitate the study of hematopoietic cell and solid organ transplantation. Spontaneously arising liquid cancers in these swine, specifically myeloid leukemias and B cell lymphomas, closely resemble human malignancies (5, 6). Raimon has characterized myeloid and lymphoid tumors in major histocompatibility characterized miniature swine and has establish aggressive tumor cell lines in vitro. With the current availability of novel genetic technologies, he aims to develop the first reliable transplantable tumor model in collaboration with Dr. Christene Huang and David Sachs.
Bringing it all together – laboratory animal medicine and animal modeling
Dr. Duran-Struuck’s expertise in laboratory animal medicine has focused on fine-tuning protocols for the care of immunodeficient large and small animals(7-9) and characterizing additional animal models. As an example, he recently immunophenotyped the lymphohematopoietic organs of naïve cynomolgus macaques and determined that B cell levels were lower than previously thought and that CD4+CD8+ T cells were constitutively activated, informing transplant researchers that changes in these populations may have not been as significant as previously believed (10).
At ULAR, Dr. Duran-Struuck is part of a phenomenal team of specialized veterinarians that provides state of the art veterinary care for animals used in biomedical research and helps investigators to design, develop, and improve their animal models. In collaboration with the University of Michigan, Temple University and NOTA laboratories, Raimon received an SBIR-NIH award to test a novel therapy for chronic rhinosinusitis. Raimon’s post-doctoral fellow Margaret Hull DVM, in collaboration with Dr. Noam Cohen (from Penn’s Perelman School of Medicine), is developing a rhinosinusitis model in rabbits. To further illustrate how laboratory animal veterinarians synergize with investigators, Caroline Blevins DVM (ULAR resident) and Jim Marx, DVM PhD, ULAR veterinarian and Assistant Professor (Pathobiology) are studying novel safe anesthetic regimens in rabbits compromised by rhinosinusitis.
Finally, in conjunction with Dr. Mason, Dr. Duran-Struuck is excited to have established a canine phoresis core at Penn Vet that utilizes phoresis protocols optimized from his published protocols in other species(8) . Under the leadership of Dr. Mason, Dr. Duran-Struuck, Vicky Anderson (BA, LVT, LATG), ULAR laboratory animal residents and other ULAR and VHUP support staff, the core has begun leukaphoresis in patients at Ryan Hospital that will help move forward novel CAR T cell and Treg therapies for canine patients. Dr. Duran-Struuck’s office is located in 177 E Old Vet Quadrangle.
References
- R. Duran-Struuck, P. Reddy, Biological advances in acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Transplantation 85, 303-308 (2008).
- D.-S. R. Hanekamp J.H., Sachs D.H., in The minipig in biomedical research, D. A. McAnulty PA, Ganderup N-C, Hastings KL, Ed. (CRC Press, 2011), chap. 23.
- R. Duran-Struuck et al., Donor Lymphocyte Infusion-Mediated Graft-versus-Host Responses in a Preclinical Swine Model of Haploidentical Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 22, 1953-1960 (2016).