Mark Atkinson: University of Florida Diabetes Center, bone marrow transplantation as a treatment for T1D, and the gut microbiome as a precipitating factor in development of T1D
by Adam Burrack, PhD
Relevant research:
PNAS 104: 2337-42, 2007
Diabetes 63: 2006-14, 2014
In our previous blogs I have described cells of the immune system, T cells, responsible for destruction of insulin-producing beta cells in the pancreas, along with several researchers who study type 1 diabetes (T1D) onset. In this addition I will focus on another prominent T1D-focused researcher and two other factors which affect the propensity to develop autoimmune disease: the bacteria that live in our intestines and the cells in our bone marrow that give rise to our immune systems.
Mark Atkinson, PhD, and his research group at the University of Florida diabetes center has been a leader in the basic science research of type 1 diabetes for over 20 years. Dr. Atkinson is director of this institute and is a Professor of Pathology and Pediatrics at the University of Florida. Among other professional roles, he is the coordinator of the nPOD consortium described in an earlier blog. Dr. Atkinson has built a career studying the context in which T1D develops in at-risk individuals, including the application of cutting-edge technologies and testing unconventional hypotheses. The immune system operates within the genetic and environmental context of the individual within whom the immune response occurs. Dr. Atkinson has built a career studying the context of the immune response in which T1D develops and has consciously focused his research on projects that could be developed into clinical therapies.
One part of the context of the immune response are the genetic differences between individuals in the cells carrying out those responses. There are many well-known genetic associations with T1D (which we will discuss in our blog about George Eisenbarth), most of which center around lymphocyte activation and the process of antigen presentation which leads to lymphocyte activation. T cells, B cells, and all other cells of the immune system in humans develop from precursor cells in the bone marrow called hematopoietic stem cells (HSCs). HSCs are long-lived progenitor cells which divide infrequently. When they do divide the resulting ‘daughter cells’ go on to develop into the various cell types of the immune system, through either the lymphoid lineage (lymphocytes include T cells and B cells, the most relevant cells for T1D onset) or the myeloid lineage (including macrophages and other cells of the innate immune system). An area of active research in the field of autoimmunity has been to study the differences in these progenitor cell types between autoimmune-prone individuals and autoimmune-resistant (normal, or ‘control’) individuals. Since gaining access to bone marrow cells from humans presents both ethical and logistic challenges, these types of studies are most often conducted in mouse strains which closely resemble the human disease of interest. For T1D, that mouse strain is the non-obese diabetic (NOD) mouse.
In a 2007 paper in the journal Proceedings of the National Academy of the United States (PNAS 104: 2337-42, 2007), Dr Atkinson’s group tested the potential utility of bone marrow transplantation for the treatment of new-onset T1D. The success of bone marrow transplantation (BMT) as a treatment would require ‘ablating’, or killing, the vast majority of bone marrow cells in the patient using total body irradiation (TBI). In effect this treatment kills the cells their immune system. Shortly thereafter patients are transplanted with bone marrow cells from a different individual. This would result in a ‘re-set button’ of sorts for the immune system in diseased individuals. This general treatment is an established method to treat childhood leukemia and has been successful. However, one potential problem with this approach is the development of graft-versus-host disease (GVHD), in which the transplanted (donor’s) blood cells attack the recipient (patient’s) cells because of genetic differences between the individuals that the blood cells will recognize. Ironically, T cells are key for GVHD to occur. In their 2007 paper, the Atkinson group used the NOD mouse model of T1D as a recipient of bone marrow/spleen cell transplants. They transplanted bone marrow cells along with CD4 T cell-depleted spleen cells into new-onset diabetic NOD mice. As a conditioning step prior to transplantation, instead of using TBI, the Atkinson group treated diabetic NOD mice to deplete T cells only prior to transplantation. The authors went on to show that this modified conditioning/deletion approach and modified transplantation approach both stopped the T cell attack on beta cells in the pancreas and promoted beta cell regeneration – leading to a return to normal blood sugar levels in previously diabetic mice without transplantation of insulin-producing cells. This study provided two important proof of principles: (1) that non-ablative ‘re-setting’ the immune system could stop autoimmunity in NOD mice, and (2) that T cell depletion followed by bone marrow transplantation can provide a window in which the endogenous beta cells could regenerate.
An emerging factor in the study of aberrant immune responses to the gut (including T1D, celiac disease, and Crohn’s disease/colitis), is the study of the bacteria residing in the intestines of affected individuals compared to non-diseased individuals. Since up to 70% of the cells of the immune system in an adult reside within or associated with the gut tube, it is logical to think that the contents of the gut – and the influence of genetics on the cells of the immune system associated with the gut – could influence immune responses both in the gut and throughout the body. Fun fact: there are 10 times as many bacteria in your intestine as there are cells comprising “your body”. Recent research suggests that the ‘microbiome’, the bacterial contents of the large intestine and small intestine, may play a role in the development of type 2 diabetes through influences on glucose metabolism in the gut and insulin sensitivity throughout the body. Outside our current scope, decreased microbial diversity in the gut is associated with impaired insulin sensitivity and development of type 2 diabetes. As a treatment to address this deficiency, some clinicians advocate ‘transplants’ of gut-derived microbes from healthy patients to the intestines of type 2 diabetic patients.
In a recent publication in Diabetes (Diabetes 63: 2006-14, 2014), Dr. Atkinson’s group compared the composition of bacteria within the intestine between individuals who developed autoimmunity compared to those who did not. In this paper, the Atkinson group compared the composition of the gut microbiome between subjects who went on to develop anti-islet autoantibodies (an early sign correlated with later development of T1D) compared to those who did not, from birth to age 3 years. They characterized differences between these two experimental groups in bacterial diversity (number of genetic families of bacteria found in the gut, fewer in those who developed T1D), microbial composition (variety of individual bacteria present from various families, fewer in those who developed T1D), or single-genus abundances (percent of total bacteria represented by any individual bacteria, higher in T1D). These differences suggest that individuals who go on to develop T1D have less genetically diverse bacterial populations within their intestines, which appears to have negative consequences for restraining T cell responses within the gut, including autoimmune T cell responses. Overall, it appears that decreased microbial diversity within the gut is associated with less restraint of inappropriate immune responses early in life, and may be associated with impaired glucose metabolism later in life. We don’t yet know the extent to which the microbial passengers in our gut tube influence disease status, but immunologists and diabetologists are shedding more light on the previously under-appreciated roles our neighbors within play in our health and wellness.