Robert Colvin, M.D.
Benjamin Castleman Distinguished Professor of Pathology
Harvard Medical School
Pathology, Massachusetts General Hospital
Physician Investigator (Cl)
Pathology, Mass General Research Institute
|MD Harvard Medical School 1968|
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. Further studies have revealed that mixed chimerism-induced tolerance leads to deletional tolerance of MHC antigens and regulatory tolerance of non-MHC antigens.
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. Dr. Colvin leads the pathology core for several NIH and industry-sponsored clinical trials as well as an international NIH genomics project in renal allograft.
A major problem in long-term organ grafts is the development of a 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 is under investigation with proteomic techniques.