MATRIX: Modular Approach to Transplant Research by Interdisciplinary Experts

To overcome the cost and side effect burden of immunosuppression, we recruited one of the pioneers of immune tolerance research, Joshua Miller, MD, in 2007 to build an immune tolerance program at Northwestern. He has succeeded in creating the program, which has transitioned to the leadership of Joseph Leventhal, MD, PhD. This program attempts to use donor-derived stem cells to induce modifications in the recipient immune system to make it friendly to both the donor organ and its recipient, eliminating the need for immunosuppressive (anti-rejection) medications. Miller’s and Leventhal’s protocols have each demonstrated operational tolerance in patients and, in spring 2012, Leventhal’s work was published in Science Translational Medicine and he was asked to deliver the opening plenary address at the American Transplant Congress. For more information, see the Immune Monitoring Core page.

Recent years have seen tremendous advances in biomarker discovery and functional genomics. From 1990-2003, the Human Genome Project mapped the human genome for the first time over the course of 13 years at a cost of more than $100 million. Now, a human genome can be sequenced for less than $10,000 and in fewer than 12 weeks. This has implications for all of medicine, including transplantation. Northwestern Transplant has partnered with world-leading functional genomics and bottom-up proteomics experts at the Scripps Research Institute, leading top-down proteomics experts at the Northwestern Chemistry of Life Processes Institute, and top industrial innovators to apply state-of-the-art biomarker discovery and validation techniques to transplant patients. Northwestern and Scripps have partnered on two major National Institutes of Health (NIH)-funded multi-center consortia to validate transplant biomarkers. They have discovered proteo-genomic biomarker signatures for both acute and chronic rejection that will abrogate, in short order, the need for biopsies, and will allow for the pre-emptive treatment of rejection, resulting in longer graft survival.

Transplantation has measured its success by basic clinical outcomes of patient and graft survival, straightforward risk adjustment, and retrospective analysis of standardized data points. But in an era of comparative effectiveness and patient-centered outcomes, the field requires more detailed and complex analysis. We have built teams of experts in health services and outcomes research, paired with transplant scientists and clinicians, to apply advanced approaches in patient-reported outcomes, decision analysis, patient safety, health informatics, informed consent, disparities and access, medication adherence, health literacy and aging to transplantation. These efforts allow us to expand measurement and analyses in more advanced ways, truly determining the comparative effectiveness of therapeutic options and improving transplant public policy and care. The end-goal of this work is to better inform patient-centered, shared decision-making for patients facing end-stage organ disease. For more information, go the Northwestern University Transplant Outcomes Research Collaborative site.

Advances in stem cell research and materials engineering have come together to create significant applications in growing and repairing human tissue. Stem cells can be used to grow specific cells on biologic or synthetic matrices, and advances in adult pluripotent cells make it possible to grow tissues that are immunologically matched to specific recipients, or even derived from their own cells. For this effort, we have brought together a transplant surgeon who is collaborating with the programs in regenerative medicine at Wake Forest and Pittsburgh, Northwestern’s departments of Materials and Biomedical Engineering, and industry experts in induced pluripotent stem cells. This team will be able to develop cells and tissues for many applications, including the creation of “just-in-time” kidneys for patients with end-stage organ failure.

The significant improvement in transplantation outcomes over the last 30 years is due mostly to a number of advances in immunosuppressive drugs. However, most immunosuppressive regimens are standardized, while it is clear different patients benefit differently from standardized approaches, and experience differential effectiveness and side effects. By studying patients’ immune systems, genetic and proteomic profiles, and self-reported outcomes instruments, we believe we can tailor immunosuppression to the individual.

The shortage of transplantable organs, with the associated waiting time and compromises in organ quality, remains the biggest single impediment to good outcomes for patients with end-stage organ failure. Our scientists are pursuing two avenues of bioengineering solutions to this problem. The first involves taking deceased-donor organs not suitable for transplantation, stripping the cells from them leaving an extracellular matrix, and repopulating them with cells developed from adult stem cells to create usable organs. The second involves developing bio-active polymer matrices and similar stem cell population to truly “grow” new organs in the lab. No longer just the stuff of science fiction, our team is working, in collaboration with other leading institutions, to make this solution to the organ shortage a reality.

Identifying adverse outcomes in transplant recipients at the time that these occur leads to a delay in treatment and lowered efficacy. Biopsies of transplanted organs can help identify issues earlier, but are expensive, invasive, and carry risks. Our team is working to validate proteo-genomic biomarker signatures that predict patients at risk for rejection and other adverse outcomes so that clinicians can intervene earlier and improve both short- and long-term outcomes. In conjunction with these efforts, our outcomes group is identifying risk factors in both donors and recipients that might indicate a good versus bad outcome following transplant.

It is well-established that access to and outcomes of transplantation are different among different racial and ethnic groups. Many of these disparities exist after correction for socioeconomic factors. Given the significant Hispanic population in the Chicago area, our Comprehensive Transplant Center has built a first-of-its-kind comprehensive Hispanic Transplant program led by Juan C. Caicedo-Ramirez, MD, that replicates the English language education and orientation in a culturally competent and congruent manner. The steadily growing program includes more than 20 bilingual and bi-cultural faculty and staff members, and has significantly increased the transplant rate in our Hispanic patients. Associated studies are ongoing to identify ways to reduce disparities in care caused by distinct cultural needs in the Hispanic population.

Industries such as finance and retail sales routinely make extensive use of data mining and predictive algorithms to leverage the information they have on their customers. Medicine has significantly more data than they do, but uses the data much less effectively. Therefore, our team is working to build a biorepository of patient samples and a database of clinical and biomarker information that, together, can power the same sort of analysis used in other industries. This will make it safer, easier and cheaper to test research hypotheses, evaluate new therapies and provide more specific information to clinicians at the point of care.

Northwestern Transplant has been a leader in the transplantation of islet cells, which requires only an infusion rather than a major surgical procedure, as an alternative to pancreas transplantation for patients with severe diabetes. In the past 20 years, our researchers have taken this from “bench to bedside,” and transformed a research procedure into an effective therapeutic option. The next phase of this work includes merging it with our research efforts in tolerance, biomarkers, outcomes and tissue engineering to make it easier on the recipients and achieve even better outcomes. Our goal is two-fold: to develop a limitless supply of insulin-producing cells and to advance tolerance of allo-transplanted islets.