Explore This Lab

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 [1, 2]. 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 [3]. 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.

Research Projects

Dr. Colvin's laboratory has been 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 [2]. The group is currently working on the transcript signatures relevant to tolerance induction.

The current focus in clinical and pre-clinical research is on the transcript patterns that reveal mechanisms of AMR, TCMR and tolerance [6, 7], with analysis of renal biopsies from patients with renal transplants and other renal diseases such as COVID nephropathy and checkpoint inhibitor toxicity, using the NanoString nCounter technology and the newly created NanoString Human Organ Transplant (HOT) probe panel [8]. The HOT panel was developed as part of an international collaborative effort led by Dr. Colvin, Dr. Micheal Mengel and Dr. Alex Loupy [9].

Group Members

Meet our research team:

  • Robert B. Colvin, MD, Benjamin Castleman Distinguished Professor of Pathology, Harvard Medical School (former chief of pathology, 1991-2006)
  • Ivy Rosales, MD, research associate, director of the histopathology core
  • R. Neal Smith, MD, PhD, assistant professor of surgery
  • Alessandro Alessandrini, PhD, assistant professor of surgery
  • Shanjuan Hong, MD, fellow
  • Qing Yuan, MD, fellow
  • Kristen Tomaszewski, MD, fellow
  • Nicole Brousaides, laboratory administrator
  • Catherine Adams, research technician II
  • Ellen Acheampong, research technician II
  • Elena Gildner, research technician II
  • Mila Araujo, research technician II
  • Kristan Scully, administrative assistant to Dr. Colvin

Selected Publications

Oh NA, T O'Shea, DK Ndishabandi, et al., Plasmacytoid Dendritic Cell-driven Induction of Treg Is Strain Specific and Correlates With Spontaneous Acceptance of Kidney Allografts. Transplantation 2020; 104:39-53.

Miyajima M, CM Chase, A Alessandrini, et al., Early acceptance of renal allografts in mice is dependent on foxp3(+) cells. Am J Pathol 2011; 178:1635-45.

Shinoda K, T Akiyoshi, CM Chase, et al., Depletion of foxp3(+) T cells abrogates tolerance of skin and heart allografts in murine mixed chimeras without the loss of mixed chimerism. Am J Transplant 2014; 14:2263-2274.

Adam BA, RN Smith, IA Rosales, et al., Chronic Antibody-Mediated Rejection in Nonhuman Primate Renal Allografts: Validation of Human Histological and Molecular Phenotypes. Am J Transplant 2017; 17:2841-2850.

Smith RN, BA Adam, IA Rosales, et al., RNA expression profiling of renal allografts in a nonhuman primate identifies variation in NK and endothelial gene expression. Am J Transplant 2018; 18:1340-1350.

Smith RN, M Matsunami, BA Adam, et al., RNA expression profiling of nonhuman primate renal allograft rejection identifies tolerance. Am J Transplant 2018; 18:1328-1339.

Matsunami M, IA Rosales, BA Adam, et al., Long-term Kinetics of Intragraft Gene Signatures in Renal Allograft Tolerance Induced by Transient Mixed Chimerism. Transplantation 2019; 103:e334-e344.

Rosales I, RN Smith, E Acheampong, et al., Routine human renal allograft biopsies analyzed for mRNA content with a novel Nanostring mRNA Human Organ Transplant (HOT) panel Am J Transplant 2020; Abstract to be presented at 2020 ATC.

Mengel M, A Loupy, C Haas, et al., Banff 2019 Meeting Report: Molecular diagnostics in solid organ transplantation - Consensus for the Banff Human Organ Transplant (B-HOT) gene panel and open source multicenter validation. Am J Transplant In press.