Pathology
Structural-protein Scrum Knocks Down Nerve Cells
Cell Biology
Study Adds Feather to mRNA Cap
Immunology
Lymph Node Cells Mimic Thymus to Induce Immune Tolerance
Ambulatory Care
Findings Cast Doubt on Association of Benzodiazepines with Hip Fractures
Medical Education
Clinical Anatomy Taught Through Surgery
T Cell–repellent Protein Protects Transplanted Tissues
High Vitamin D Levels Linked to Lower Risk of MS
Joslin Appoints Ranch Kimball as Seventh President
New Education Deans Named at HSPH
International Network to Study Heart Disease
Quad Professorship Energizes Medical Communications
T Cell–repellent Protein Protects Transplanted Tissue
Murine insulin-producing islet cells made to express stromal-derived factor-1 (SDF-1) and transplanted into allogeneic mice resisted T cell responses to the graft, ensuring its prolonged survival. This observation was made by Natalia Papeta and Tao Chen, research fellows in the laboratory of Mark Poznansky, HMS assistant professor of medicine, and colleagues at Massachusetts General Hospital. The research appears in the Jan. 27 issue of Transplantation.
In a previous study, Poznansky had found that T cells are repelled by high concentrations of the chemokine SDF-1 via a mechanism termed fugetaxis. This property mirrors the protein’s physiological role in the thymus, where a high concentration of SDF-1 facilitates the exit of mature T cells into the peripheral circulation. In the present study, the investigators aimed to exploit the repellent properties of SDF-1 to prevent T cell infiltration of the transplanted tissue and thereby prolong graft survival.
By using the chemorepellent properties of SDF-1 for T cells, the researchers created a local niche where the transplanted tissue could avoid alloreactive cell-mediated responses and remain healthy. |
The team first induced diabetes in recipient mice. Following the introduction of allogeneic insulin-producing islet cells transduced with SDF-1 into the mice, their levels of blood glucose were scored to determine the function of the transplanted tissue. The ability of the tissue to normalize blood glucose levels was used as an indicator of its survival and overall health in the recipient animals. In 80 percent of the mice expressing a high amount of SDF-1, blood glucose levels returned to normal. But mice that were SDF-1 negative were unable to demonstrate this effect due to destruction of the allograft. At the cellular level, success of the graft was manifested as a clearly evident reduction of alloreactive–T cell infiltration into the transplanted tissue that expressed a high level of SDF-1. In vitro model systems demonstrated that high concentrations of SDF-1 primarily blocked the migration of alloreactive cytotoxic T cells into the donor tissue.
The primary aim of this work was to utilize high concentrations of SDF-1 to achieve “immune isolation” for the transplanted tissue, said Poznansky. The method differs conceptually from existing methods of immunosupression that are widely used to alleviate immune responses to allografts. By using the chemorepellent properties of SDF-1 for T cells, the researchers created a local niche where the transplanted tissue could avoid alloreactive cell-mediated responses and remain healthy. This novel approach could potentially obviate the need for immunosuppressive drugs and the inevitable systemic effects associated with their use. As a next step, Poznansky hopes to extend these results to non-obese diabetic mice, which offer a close parallel with human type 1 diabetes.
This research was funded by the Juvenile Diabetes Research Foundation and the National Institutes of Health.
High Vitamin D Levels Linked to Lower Risk of MS
The first large-scale study that examines the association between circulating vitamin D and multiple sclerosis (MS) predicts a lower risk of this neuropathy in individuals having a high serum concentration of vitamin D. The study was published in the Dec. 20, 2006, issue of the Journal of the American Medical Association and conducted by Kassandra Munger, a doctoral student in nutrition, and Alberto Ascherio, HSPH associate professor of nutrition and epidemiology.
The research was done in collaboration with the U.S. military, which provided access to serum samples of 7 million active-duty military personnel collected since 1990. The investigators identified 257 cases of MS occurring among Army and Navy personnel between 1992 and 2004.
Previous studies that have attempted to address the link between vitamin D and MS risk have either been retrospective and have relied largely on patient history to determine early-life exposure to sunlight, and therefore vitamin D, a method that is open to erroneous information, or focused only on dietary intake of vitamin D. In the present prospective study, the researchers measured serum concentrations of 25-hydroxyvitamin D, a good indicator of vitamin D availability to tissues, in two or more serum samples from each of the MS patients collected over a course of a few years prior to their MS onset and in controls who were drawn randomly from the population. The data obtained were analyzed to assess risk of MS as a function of serum vitamin D levels.
This study found that, among whites, those in the top 20 percent of vitamin D levels (>99.1 nmol/L) had a 62 percent lower risk of MS compared to individuals with levels in the bottom 20 percent (<63.3 nmol/L). The association was strongest in whites less than 20 years old. A similar association was absent in African-American and Hispanic populations, likely due to smaller sample sizes and intrinsic lower levels of vitamin D in these populations.
An extension of this research will involve charting a dose–response curve to assess levels of vitamin D required to confer protection against MS. Such a study could pave the way for broad intervention strategies to lower the risk of disease in susceptible populations.