Transplant Pathology Clinical Fellowship Program

The Division of Transplantation Pathology offers a one or two year fellowship program with the following mission:

1. To train the fellow in interpretation of native and allograft liver, kidney, heart, pancreas, intestinal and composite tissue biopsies as well as resection specimens.
2. To impart confidence in performing intra-operative surgical consultations (frozen sections).
3. To teach the necessity of clinical-pathological correlations in arriving at meaningful surgical pathology diagnoses.
4. To facilitate familiarity with modern molecular biology techniques that are revolutionizing laboratory medicine.
5. To make the fellow familiar with data collection, statistical analysis, formal scientific presentation, and publication.
6. To provide experience in teaching medical students and residents.

The Division is strongly devoted to teaching and training in transplantation pathology. Our faculty holds numerous NIH funded transplant related grants and are available to train our fellows in transplant pathology for a career in academic medicine.

As members of the Thomas E. Starzl Transplantation Institute, we work closely with surgeons and clinicians both in research and clinical practice.

The Division has established and maintains an active telepathology consultation service with HIPAA-compliant software.

Our faculty routinely speaks at national and international meetings, including: United States and Canadian Academy of Pathology; Federation of American Societies for Experimental Biology; American Society of Transplantation; International Society for Heart and Lung Transplantation; College of American Pathologists; The American Society of Transplant Surgeons; American Society for Investigative Pathology; American Medical Informatics Association; American Association for the Study of Liver Diseases and The Transplantation Society and are members of the Hans Popper Hepatopathology Society; Renal Pathology Society; American Society of Nephrology; American Society of Microbiology; Transplant Infectious Disease Society; American Society of Clinical Pathologists; American Association for Advancement of Science; American Association of Pathologists; Histiocyte Society; International Academy of Pathology; International Association for Research on Epstein Barr Virus and Associated Diseases.

Our division routinely collaborates with the following Institutions: The University of Pittsburgh Transplantation Institute renamed the Thomas E. Starzl Transplantation Institute (STI); Carnegie Mellon Robotics: Medical Robotics Technology Center (MRTC); McGowan Institute for Regenerative Medicine; Hillman Cancer Center. These institutions assist in providing advances in patient care and research. The laboratories are in close proximity to the transplant pathology general sign-out area. This facilitates collaboration on projects and allows our transplant fellow to attend many of the Starzl Transplant Institute research talks and symposiums.

Twenty eight (28) of the fifty-two (52) weeks of the one-year of fellowship is dedicated to the evaluation of biopsies taken from patients who have undergone heart, liver, pancreas, kidney, composite tissue, small intestine and multivisceral transplantation, as well as their explanted organs. Liver and extra-hepatic biliary tree specimens from all UPMC hospitals are triaged to our division for diagnosis. We have a busy consultation service and participate in native kidney evaluation as well. The fellow may devote twenty (20) of the fifty-two (52) weeks to a research project and/or elective rotations. The department strongly encourages the fellow to attend a national conference by providing both funding and time off.

The following description of ongoing research activities illustrates the variety of projects available for participation:

1. The division evaluates tissue specimens from operationally tolerant liver allograft recipients. The specimens are from our own patient population and from sites involved in national and international multicenter studies of tolerance induction. Novel techniques are being applied to the evaluation of these specimens such as multiplex quantum dot labeling followed by high resolution whole slide imaging and automated morphometric analysis. These results rely heavily on histopathologic and multiplex marker evaluation.
2. Studies on the role of IL-6/gp130 signaling in liver diseases continue with a specific interest in a family of molecules, small proline rich proteins, which function as SH3 domain ligands that protect cells from oxidative stress and induce epithelial-mesenchymal transition in biliary epithelial cells. Work during the past year shows that these molecules play important roles in the cellular response to stress, wound healing and migration, and neoplasia by interacting with a number of biologically important cell stress (e.g. p53) and regulatory proteins through SH3 domain binding and other binding domains.
3. The division has investigated significant time and monetary resources toward the development of digital pathology including multiplex staining of tissue specimens followed by high resolution whole slide imaging and automated image analysis. The division has several scanners fully equipped for a combination of brightfield and multichannel fluorescence imaging, as well as a system for 2 and 3 dimensional digital analysis of multiplex-labeled samples. This effort has supported multiple investigators throughout the University of Pittsburgh and we are currently collaborating with several external groups on various studies.
4. Alloantibodies in Liver, Kidney, and Cardiac Transplantation – Intervention, Outcomes and Mechanisms Antibodies directed against allograft antigens are being increasingly recognized as critical determinants of allograft outcomes in adults. Pediatric heart transplant candidates are frequently allosensitized based on prior exposure to blood products and homografts. To overcome the high wait-list mortality, transplantation across a donor-specific cross-match has recently been performed in several pediatric centers, with early encouraging results. This application brings together a group of six leading heart transplant centers and leading transplantation scientists to study the impact of preformed and de novo alloantibodies on pediatric heart transplant outcomes. A major effort during the past two years also resulted in a major publication of the role of allo-antibodies and C4d staining in liver allografts.
5. The Research Histology Laboratory of the Division serves as the Core Laboratory for three separate PO1 grants and one NIH contract: 1) Liver Tissue Core Laboratory Contract for the Immune Tolerance Network (ITN), which covers both 3 currently active liver and one currently active kidney transplantation trials; 2) Histopathology Core for the PO1 grant entitled, “Peripheral Mechanisms of Tolerance”; 3) Liver Antigen Presenting Cells in Hepatic Injury and Transplantation; and 4) the Histopathology Core the PO1 grant entitled, “Allo-antibodies in Cardiac Transplantation-Intervention, Outcomes and Mechanisms”. Specific Web-based software has been developed to communicate results to investigators throughout the world on a real time basis. Data management tools are being developed for this application.
6. The gut bacteria and microbial associated molecular patterns (MAMPs) play an important role in liver (patho-) physiology including metabolism, drug detoxification, and immune surveillance, including maturation of dendritic cells. Studies are underway to better understand the role of these MAMPs in recruiting resident non-parenchymal cells, including Kupffer, NK, and NKT cells within the liver.
7. The clinical profile of patients with BK virus infection in the renal allograft is defined. DNA sequencing of viral strains is being used to define mutations and genomic rearrangements, which may be relevant to the pathogenesis of an extremely refractory interstitial nephritis seen in these individuals. Quantitative PCR assays have been developed to measure viral load in biopsy samples and body fluids to better manage the immunosuppression levels in these patients. The interplay between host and viral immune factors in this disease is being investigated by DNA microarray technology. Drugs with antiviral activity are being screened in an in-vitro culture model for possible future use in the clinical arena.
8. Another important area of research is the pre- and post-transplant sensitization of solid organ transplant recipients. We are interested to evaluate the development of anti-HLA and non-HLA antibodies in transplant recipients and the impact of various immunosuppressive strategies. The overall immuno-competence and the specific memory responses to various pathogens is an important aspect of patient management post-transplantation and assays are developed to assess the risk of infection and the extend for prophylaxis required based on the immune reactivity.
9. Clinical research of antibody-mediated immune response in solid-organ transplantation is another area of investigation. The detection and specificity analysis of pre-formed and post-transplant developed antibodies are important components of humoral allo-response dynamics, while outcome association reveals the clinical impact of humoral/mixed forms of graft rejection. I am also interested in additional markers of antibody-mediated rejection (like soluble forms or vascular C4d deposition), as well as in the influence of various therapeutic protocols on HLA and non-HLA antibody response, both in adult and pediatric transplant populations.
10. We continue to investigate the pathophysiology of allograft dysfunction after liver, kidney, heart, intestinal, and composite tissue transplantation. Examples include evaluation of donor biopsies in suitability of organs for transplantation, recurrence of native and new diseases after transplantation, enhanced methods or diagnoses of causes of allograft dysfunction, such as multiplex staining of tissue for markers of interest that correlate with immunologic effector mechanisms or cellular responses to injury and repair.
11. A computer algorithm, HLAMatchmaker, has been developed that assesses donor-recipient HLA compatibility at the epitope level. It considers so-called eplets as essential components of antibody-defined HLA epitopes. Ongoing studies have provided a new understanding of the structural basis of HLA epitope antigenicity (its ability to react with antibodies) and immunogenicity (its ability to elicit and antibody response). HLA matching at the epitope level is relevant for transplantation.