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Overview

The mechanisms of graft acceptance (tolerance) have been a major area of investigation in the transplant group at Mass General, with mouse, pigs, non-human primates and most recently a clinical trial. Dr. Colvin is currently seeking the mechanisms of graft acceptance and the role of Foxp3+ Treg cells in mouse kidney allografts. These studies have revealed a novel Treg-rich organized lymphoid structure (TOLS) in accepted allografts that surround small arteries. Depletion of Treg causes dissolution of the TOLS and precipitates acute graft rejection. Further studies have revealed that mixed chimerism-induced tolerance leads to deletional tolerance of MHC antigens and regulatory tolerance of non-MHC antigens. Current studies are focused on the mechanism of kidney-induced tolerance using mRNA Nanostring analysis.

In studies in human kidney allografts, Dr. Colvin’s group was the first to describe chronic antibody-mediated rejection, now recognized as the most common cause of late graft dysfunction. He has shown that deposition of the classical complement component, C4d, in peritubular capillaries is a useful marker of acute and chronic antibody-mediated rejection. C4d is the most specific marker of these conditions. Through the efforts of Dr. Colvin and others, new categories of acute and chronic antibody-mediated rejection have been incorporated into the Banff criteria and have become the standard of care. Protocol biopsies from non-human primate studies have demonstrated sequential stages of chronic humoral rejection and tolerance with distinctive mRNA signatures.

A major problem in long-term organ grafts is the development of chronic arteriopathy, which has an unknown pathogenesis. Dr. Colvin and Dr. Paul Russell developed and characterized a model of the disease, using heart grafts in mice. Coronary arteries develop florid lesions over 4-8 weeks, resembling closely the lesions in human organ grafts. The group showed that chronic allograft arteriopathy can be produced by three distinct immune pathways, humoral antibody (passive transfer of anti-donor antibodies into RAG-1 knockout mice), T cells (male to female grafts) or natural killer cells (parental graft to F1 recipients). Such antibodies can mediate chronic arteriopathy in the absence of complement, through an NK cell-dependent FcR mechanism.

The immunopathogenesis of renal diseases is Dr. Colvin’s other long-term interest. He has recently identified a new disease due to anti-brush border antibodies (ABBA) that deposit in the proximal tubules. The publication led to the discovery of several other cases. The nature of the antigen was recently identified as megalin.

Research Projects

Dr. Colvin's laboratory is now primarily focused on the role of T regulatory cells (Foxp3+) in spontaneous acceptance of renal allografts in mice. Stable grafts have a characteristic T and B cell lymphoid aggregates around arteries with abundant Foxp3+ cells, which have been termed Treg-rich organized lymphoid structures (TOLS), believed to be important in acceptance. In recipients with stable renal allografts, transient depletion of Foxp3+ cells precipitates rapid and severe acute cellular rejection.

The group is currently working on the mechanisms by which TOLS arise and the loss of Foxp3+ cells promotes rejection. New techniques include in vivo imaging of the cellular activity in renal allografts, using a minimally invasive, novel confocal multicolor endomicroscope developed by a co-investigator, Seok Yun, PhD, at Mass General, which can detect cells labeled with fluorescent proteins and dyes.

Group Members

Meet our research team:

  • Robert B. Colvin, MD, Benjamin Castleman Distinguished Professor of Pathology, Harvard Medical School (Formerly Chief of Pathology, 1991-2006)
  • Alessandro Alessandrini, PhD, Associate Director, Pediatric Surgical Research Laboratories  
  • Ivy Rosales, MD, Fellow
  • Chao Yang, MD, Fellow
  • Patricia Della Pelle, Laboratory Administrator
  • Catherine Adams, Administrative Assistant to Dr. Colvin
  • Nicole Brousaides, Research Technologist
  • Rebecca White, Research Technician II
  • A. Bernard Collins, Technical Director
  • Dorothy Ndishabandi, Research Technician II

Selected Publications

Smith RN, Adam BA, Rosales IA, Matsunami M, Oura T, Cosimi AB, Kawai T, Mengel M and Colvin RB. RNA expression profiling of renal allografts in a nonhuman primate identifies variation in NK and endothelial gene expression. Am J Transplant. 2018; In Press.

Larsen CP, Trivin-Avillach C, Coles P, Collins AB, Merchant M, Ma H, Wilkey DW, Ambruzs JM, Messias NC, Cossey LN, Rosales IA, Wooldridge T, Walker PD, Colvin RB, Klein J, Salant DJ, Beck LH Jr. Low-density lipoprotein receptor-related 2 (megalin) as target antigen in human kidney anti-brush border antibody disease. J Am Soc Nephrol. 2018; 29: 644-653.

Sprangers B, DeWolf S, Savage TM, Morokata T, Obradovic A, LoCascio SA, Shonts B, Zuber J, Lau SP, Shah R, Morris H, Steshenko V, Zorn E, Preffer FI, Olek S, Dombkowski DM, Turka LA, Colvin RB, Winchester R, Kawai T and Sykes M. Origin of enriched regulatory T cells in patients receiving combined kidney-bone marrow transplantation to induce transplantation tolerance. Am J Transplant. 2017; 17:2020-2032.

Role of complement and NK cells in antibody mediated rejection. Akiyoshi T, Hirohashi T, Alessandrini A, Chase CM, Farkash EA, Neal Smith R, Madsen JC, Russell PS, Colvin RB. Hum Immunol. 2012 Dec;73(12):1226-32.

Early acceptance of renal allografts in mice is dependent on foxp3(+) cells. Miyajima M, Chase CM, Alessandrini A, Farkash EA, Della Pelle P, Benichou G, Graham JA, Madsen JC, Russell PS, Colvin RB. Am J Pathol. 2011 Apr;178(4):1635-45.