Explore This Lab

Overview

The mechanisms of graft acceptance (tolerance) have been a major area of investigation in the
transplant group at MGH, 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. Colvin’s group showed that
kidney allografts induce systemic tolerance within two weeks that allows subsequent acceptance
of heart allograft. Systemic tolerance is dependent on Foxp3 cells. Current work addresses the
molecular mechanisms by which kidneys induce tolerance.

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. Non-human primate studies have
demonstrated sequential stages of chronic humoral rejection and tolerance with distinctive
mRNA signatures as detected by Nanostring analysis of protocol biopsies. This approach is now
being applied to human renal transplant biopsies in a protocol to induce tolerance.

The immunopathogenesis of renal diseases is Dr. Colvin’s other long-term interest. His group
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 and identification of the target antigen megalin. Recent studies have identified collapsing focal segmental glomerulosclerosis as a cause of progressive renal disease in patients with COVID-19 who have
APOL1 risk alleles.

The major focus of the laboratory currently is the transcript analysis of human renal biopsies,
both transplanted and native kidneys. The technique employs the NanoString nCounter to
assess ~800 genes in routine formalin fixed paraffin embedded tissues. Among the advantages of NanoString are that a separate core, processed at the time of biopsy, is not required. Transcripts are assessed in the same sample analyzed by light microscopy and large retrospective and longitudinal analyses of archived samples can be readily performed in the setting of multicenter studies, which will enable retrospective randomization with long-term survival endpoints available. Dr. Colvin is one of the leaders of an international consortium that has developed a novel Human Organ Transplant (HOT) panel to accelerate translational research and will be applying this approach to >1000 clinical samples.

Selected Publications

Mengel, M, Loupy A, Haas C, C. R, Naesens M, Akalin E, Clahsen-van Groningen MC, Dagobert J, Demetris AJ, Duong van Huyen JP, Gueguen J, Issa F, Robin b, Rosales I, Von der Thüsen JH, Sanchez-Fueyo A, Smith RN, Wood K, Adam B and Colvin RB. 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, 20: in press, 2020.

Hu H, Larsen C, Hernandez-Arroyo CF, Mohamed MMB, Caza T, Sharshir M, Chughtai A, Zie L, Gimenez JM, Sandow TA, Lusco MA, Yang H, Acheampong E, Rosales IA, Colvin RB, Fogo A, Velez JC. Acute kidney injury and collapsing glomerulopathy associated with COVID-19 and APOL1 high risk genotype. J Am Soc Nephrol, in press, 2020.

Oh NA, Ndishabandi DK, Yuan Q, Hong S, Gans J, Ge J, Gibney S, Chase C, Yang C, Rosales IA, Shinoda K, Drew B, Kojima L, Russell PS, Madsen JC, Colvin RB, and Alessandrini A. Plasmacytoid dendritic cell driven induction of Treg is strainspecific and correlates with spontaneous acceptance of kidney allografts. Transplantation 104:39-53, 2020.

Matsunami M, Rosales IA, Adam BA, Oura T, Mengel M, Smith RN, Lee H, Cosimi AB, Colvin RB, and Kawai T. Longterm kinetics of intragraft gene signatures in renal allograft tolerance induced by transient mixed chimerism , Transplantation 103:e334-e344, 2019.

Smith RN, Adam BA, Rosales IA, Matsunami M, Oura T, Cosimi AB, Kawai T, Mengel M and Colvin RB. RNA expression profiling of nonhumanprimate renal allograft rejection identifies tolerance. Am J Transplant 18: 1328-1339, 2018.