The Transplant Institute
Beth Israel Deaconess
Islet resident macrophages are immunoregulatory and prolong islet transplant survival
Thomas B Thornley1, Periklis P Kyriazis1, Krishna A Agarwal1, Lingzi Ma1, Vaja Chipashvili1, Terry B Strom1, Maria Koulmanda1.
1aDepartment of Medicine bDepartment of Surgery, Harvard Medical School,, Transplant Institute at Beth Israel Deaconess Medical Center, Boston, MA, United States
CD169+ tissue-resident macrophages induce antigen-specific Tregs and exert immunoregulatory function in transplantation and asthmatic lung inflammation. We have now identified a CD169+ tissue-resident macrophage subset that dwells in the pancreatic islets of untreated, non-autoimmune C57BL/6 mice and non-diabetic humans. To compare the phenotype of islet resident macrophages (IRMs) and islet resident dendritic cells (IRDCs), we FACS-sorted IRMs and IRDCs from mouse islets and performed qPCR analysis. Akin to other populations of tissue-resident macrophages, we also detected higher levels of immunoregulatory CD39, CD73 and galectin-9 in IRMs relative to IRDCs. To compare the functional influence of IRMs and IRDCs over T cell differentiation, we cultured IRMs and IRDCs from bm12 (I-Abm12) mice in the mixed lymphocyte reaction at a 1:20 ratio with naïve CD4+ ABM TCR transgenic T cells that express a clonotypic anti-I-Abm12 TCR. IRMs from bm12 mice induced less proliferation in transgenic CD4+ T cells when compared to IRDCs. Strikingly, IRM stimulators induced 20.9 +/- 6.12% of activated CD4 T cells to express FoxP3 as compared to 3.41 +/- 1.61% of IRDC stimulated T cells or 2.07 +/- 0.66% of splenic DC stimulated T cells in 5 independent experiments. Previously, we have shown that TIM-4 blockade improves the survival of tissue-resident macrophages thereby prolonging heart allograft survival . Importantly, we found that blockade of TIM-4 prolonged the survival of fully allogeneic islet allografts (MST=43 days, n=5) when compared to wild type islets transplanted into wild type mice (MST=17 days, n=4, p<0.05) . Furthermore, 2/5 transplants in the TIM-4 blockade group lasted >110 days whereas all mice in the control group rejected by day 10. We have identified a novel subset of immunoregulatory IRMs that powerfully induces Tregs and prolongs islet transplant survival.
 Thornley et al. J Clin Invest. 2014; 124(8): 3443–3454.
15:30 - 17:00
|Immunology||Islet resident macrophages are immunoregulatory and prolong islet transplant survival||Room 111-112|