by Adam Burrack, PhD
Benaroya Institute, Immune Tolerance Network, Dr Gerald Nepom MD, PhD
I’ve profiled several world-renowned type 1 diabetes research-focused institutions in our “immunology of diabetes” blog series and today will describe another. So far we’ve learned about the Barbara Davis Center in Denver, the Joslin Institute in Boston, and the UCSF diabetes center. Today I highlight the Benaroya Institute in Seattle and specifically the research program of director Gerald Nepom. Dr Nepom has been a leader in the field of clinical immunology, and type 1 diabetes research in particular, for over 20 years. The Benaroya Institute employs researchers who cover the continuum from basic immunology questions to clinical trials. The Benaroya is one of several institutions conducting large-scale clinical trials of immune system-directed therapeutics.
Dr Nepom also has the distinction of being the current director of the Immune Tolerance Network, a research consortium dedicated to developing a better understanding of how the immune system differentiates between self and non-self. The immune tolerance network (ITN), has physical locations at the Benaroya in Seattle, UCSF, and the NIH. ITN has a three-part mission: to develop a better understanding of how immune tolerance operates in health and is perturbed in disease states, to leverage that knowledge into development of new therapeutics, and to improve clinical management of human disease, including a well-articulated strategic plan to pursue T cell-directed therapies for the prevention or cure of type 1 diabetes. Dr Nepom plays a key leadership role with both of these groups.
The Benaroya Institute is dedicated to studying immune-mediated diseases including type 1 diabetes, multiple sclerosis, Crohn’s and lupus. Located in Seattle, Washington, researchers at Benaroya have the opportunity to collaborate with the well-regarded University of Washington immunology department – at which Dr Nepom has an appointment – as well as several local industry firms including biotechnology giant Amgen and pharmaceutical titan Novo Nordisk. As such, the Benaroya is uniquely placed to play a role in conducting important clinical trials for promising immune system-directed therapies.
Dr. Nepom’s published research covers the spectrum of immune system-related topics relevant to type 1 diabetes. As a physician-scientist Dr Nepom‘s research is as broad as the Benaroya Institute’s: he has published on signaling pathways within autoreactive T cells as well as on the results of clinical trials. Several brief recaps of recent publications on which Dr Nepom has been an author follow.
Similar to a paper I described from the St Vincent’s Institute in Melbourne, Australia (Thomas Kay blog post), researchers at the Benaroya Institute are working on developing reagents to track proinsulin-specific CD4-expressing T cells. In a publication in the journal Plos One this past May, researchers at Benaroya described a relationship between a known risk allele – a protein that promotes growth receptor signaling in T cells and could promote expansion of T cells during development in the thymus – and accelerated development over time of autoreactive T cells specific for pro-insulin. The patient population studied in this article all possessed the high-risk HLA molecule I’ve previously described, and which tetramer-tracking technology relies on. The additional genetic risk factor described promotes survival and expansion of T cells that otherwise would not leave the thymus. This research demonstrating stratified risk levels may help explain why some individuals with the high-risk HLA-DR4 genotype develop type 1 diabetes earlier in life than others. Those who develop disease earlier may have the additional risk factor described in this study, whereas DR4-positive individuals who develop disease later in life may possess the ‘protective’ form of this gene.
One component of a biologic cure for type 1 diabetes is removing or inhibiting autoreactive T cells. Researchers across the world are zeroing in on methods to specifically address ‘memory’ T cells in the clinic. In a recent publication, Dr Nepom and others described a clinical trial of CD2 blockade in new-onset diabetic patients, which is a new attempt to remove autoreactive T cells from patients in the clinic. CD2 is a molecule that is expressed more highly on the cell surface of ‘central memory’ T cells than other types of T cells. In the clinical trial patients were treated with an antibody that binds to CD2 and inhibits CD2-expressing T cells from acting. Researchers observed slightly higher C-peptide production, slightly decreased daily insulin usage, and fewer hypoglycemic events in patients treated with CD2 blockade than with placebo (negative controls). However, the primary end-point of the study was HbA1c, the accepted measure of long-term blood sugar level management, which did not change between treated and untreated participants.
Another – less specific – potential clinical strategy to promote increased insulin sensitivity is the blockade of pro-inflammatory cytokines. This treatment is less ideal because cytokines are signaling molecules of the immune system. Similar to hormones, cytokines regulate the behavior of multiple cells and tissue types, but during immune responses rather than development. As treatment for T1D, the timing and anatomical location of anti-cytokine treatments are key as described in a recent review article by Dr Nepom and colleagues. By the time disease has occurred blocking cytokines in the blood may do more harm (promoting infections, inhibiting the overall immune response) than good (promoting insulin sensitivity). One time when cytokine blockade may be useful is right around the time of beta cell replacement.
A key component of a biologic cure for type 1 diabetes is replacement of insulin-producing beta cells through transplantation. Memory T cells are critical for protection against viruses and bacteria, but in the case of type 1 diabetes, autoreactivity against the pancreas impairs the ability to ‘induce’ immune tolerance to transplanted pancreatic beta cells. Dr Nepom recently authored an opinion article on this topic in the American Journal of Transplantation. What the above means is that memory T cells resist therapies that restrain responses by ‘naïve’ T cells. Unfortunately, candidate therapies from basic research are usually studied – at least initially – in animal models that are not autoimmune diabetic. When applying these therapies to the autoimmune animal models most therapies fail, miserably. This is due to the presence of ‘memory’ T cells, which are more easily activated to respond than naïve T cells and resist the effects of therapies. Dr Nepom, and others, would argue that this is a property of memory T cells in general, not only autoreactive T cells, and that we need to use different models to study how to inhibit the actions of memory T cells.
Dr Nepom’s career is an excellent example of the progress that a well-trained physician-scientist can accomplish over the course of a career. At YOUglycemia we applaud the efforts of Dr Nepom and others at the Benaroya Institute and the Immune Tolerance Network and look forward to the next wave of discoveries!