American Transplantation Congress meeting, May 2-6, Philadelphia, PA
by Adam Burrack, PhD
This past week I had the opportunity to present research from my dissertation in the laboratory of Ron Gill at the University of Colorado at the American Transplantation Congress 2015 meeting. I will be sure to let our readers know when my work with Dr. Gill is published. As a teaser, I investigated the mechanisms of how pancreatic islet transplants are destroyed in autoimmune diabetic mice (the NOD mouse, which I’ve described previously). Since the clinically relevant scenario is an islet transplant from a genetically unrelated donor (called an allograft), into a currently diabetic animal, I studied the role of the MHC molecule (as I’ve described previously this is the molecule that ‘shows’ peptides to T cells of the immune system, and therefore has a big role in starting immune responses) as a target of the immune response in transplant recipients. When transplanting insulin-producing cells into a diabetic animal (or person) there will be two categories of immune response: (1) the response against the different MHC (called HLA for humans) which is present in any transplant scenario, and (2) the response of autoreactive cells against beta cell-derived peptides (which caused T1D in the first place). Both of these immune responses are mediated by T cells. The first type of T cell response against transplanted beta cells into an animal (or person) with T1D – against transplant MHC/HLA – is called “alloreactivity” and is the general reason that transplants are rejected and that immune suppression is required to prevent transplant rejection of any organ. The second reason, autoimmune T cells, are a special case in the individual with T1D and must also be addressed clinically. I will save a recapitulation of my results for a future post in this series.
ATC is the annual meeting of transplant surgeons, transplant physicians, and basic scientists working to develop better solutions for clinical transplantation. Whole pancreas and pancreatic islet transplantation were major subjects at this meeting, along with another organ very relevant to our readers, kidney transplantation. It’s always interesting to me to observe the different ways disciplines collect analyze data. Clinical researchers are fantastic at generating questions that are relevant and useful to investigate. In contrast, sometimes basic science researchers will investigate what they find interesting, rather than something that is clinically applicable. However, basic researchers really shine when it comes to having cool tools to address questions, using animal models, cutting-edge methods and reagents, and the latest tools for data analysis. These broad differences between clinical research and basic research make this type of combined meeting both frustrating and really useful – for both parties.
In addition, there is a sub-society of ATC, IPITA (International Pancreas and Islet Transplantation Association) which meets every other year and specifically gathers researchers, physicians, and surgeons who specifically study pancreas and islet transplantation. This year is a meeting year for the IPITA group, in Melbourne, Australia. I had the opportunity to attend this meeting in September 2013 with Dr. Gill to present some of my work. It was a great experience to meet the researchers whose work I regularly read face-to-face, ask questions, and learn the field more thoroughly.
What follows is a brief report on some of the talks I attended at the ATC conference in Philadelphia. Four different types of beta cell replacement were discussed at this meeting. First I’ll briefly describe islet xenotransplantation, which is pig islets transplanted into humans with T1D. Second is the most common form of islet transplant, human allografts. For allografts, islets from (unrelated) deceased human donor are transplanted into an individual with T1D. Third and not relevant to this discussion are islet autografts. For acute severe pancreatitis patients only: surgeons will remove the inflamed pancreas and digest away the exocrine tissue to yield pure islet preparations and put those islets back into the patient. The patient will require digestive enzyme pills for the rest of their life. Fourth, stem cell-derived beta cells as a long-term possibility in the clinic.
Bernard Herring from the University of Minnesota gave an interesting talk about islet xenotransplantation. The Schulze Diabetes Institute at the U of MN has been pursuing this track for a number of years. Pigs represent a nearly endless supply of pancreatic islets for transplantation. However, xenorejection (due to species differences on transplanted cells between pig donor and human recipient) lead to very strong T cell responses which must be strongly suppressed for the life of the recipient. These strong anti-rejection drugs are a current limiting factor for the wide-spread application of xenogeneic islets. Development of improved immune suppression protocols is an active area of research and development.
The human pancreas transplant group at the University of Indiana continues to experience great success. This group performs whole pancreas transplants into individuals with T1D, which does require life-long immune suppression treatment but can ameliorate hypoglycemic unawareness. Dr. Jonathan Fridell from this group gave several excellent presentations describing their results and their clinical program. Unfortunately for transplant recipients, the anti-allograft response is nearly as strong as the anti-xenograft response, and also requires strong immune suppression.
Nicholas Zavazava’s lab at the University of Iowa is doing some interesting work in the iPS cell field. Similar to Doug Melton’s group at Harvard, Dr Zavazava’s group is working to develop iPS cell lines to be made (or “differentiated”) into insulin-producing beta cells for transplantation purposes. A graduate student from Dr Zavazava’s group gave an excellent presentation of her work. A key next step with this research – for all groups taking this approach – is proof-of-principle studies in diabetic mice. It will be a key testing ground to see whether these “derived” beta cells can reverse diabetes in autoimmune mice. A second-level question – and one that requires an answer before this strategy could move forward into the clinic – is to determine what the T cell response is against these insulin-producing cells in autoimmune mice.
Dr. Jon Odorico from the University of Wisconsin transplant program gave an excellent overview of the current state of the art in the field of “directed differentiation” of iPS cells to beta cells. In particular, he discussed the methods from a Nature Biotechnology paper published in November 2014 by the company Betalogics. This protocol yields broadly similar cells to results published by Doug Melton from Harvard last October, but with a different protocol which may yield more consistent results.
My take-home from this meeting: we are entering an exciting time in the history of beta cell replacement therapies, one in which the immune response to engineered insulin-producing cells will be key to understand – and to control – for these candidate therapies to take the next step into the clinic. In fact, one might speculate that one day in the not-too-distant future, pancreas and islet transplantation will no longer be necessary. Given the appropriately cautious nature of the FDA regulatory process, that day is probably decades away, but these cross-discipline meetings are all about building the future of medicine. The ATC was a great meeting to attend to learn about the current cutting edge of the field, and to talk with colleagues about where we are headed next.