Over the last 30 years research from Dr. Colvin's group has led to new strategies to prevent, diagnose, and treat renal allograft rejection. Subjects for these studies range from mouse, pig and monkey to man and heart and kidney grafts. Over 40 research fellows have received training in his laboratory and he has had continuous NIH funding since 1976. The principal themes in this research are the elucidation of the role of antibodies in graft rejection and the mechanisms of graft acceptance.
Acute and chronic antibody-mediated rejection (human, monkey and mouse studies)
Dr. Colvin's group discovered that the deposition of the classical complement component, C4d, in peritubular capillaries is a reliable marker of acute and chronic antibody mediated rejection. C4d is more specific and sensitive than traditional criteria and is a potentially valuable adjunct in the diagnosis of graft dysfunction. Through the efforts of Dr. Colvin and others, the new categories of acute and chronic antibody mediated rejection has been incorporated into the Banff criteria and has become the standard of care. His group provides the reference pathology laboratory for several large NIH-funded multicenter trial groups, including Collaborative Trials in Organ Transplantation, Genomics in Chronic Allograft Rejection, Immune Tolerance Network (ITN) that will assess outcomes and predictive pathological and molecular markers in novel drug regimens.
A major problem in the long-term organ graft is the development of a chronic arteriopathy. Dr. Paul Russell of the Transplantation Unit and Dr. Colvin developed and characterized a model of the disease using heart grafts in mice, in order to identify mechanisms. Coronary arteries develop florid lesions over 1-2 months, 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 knock out mice), T cells (male to female grafts) or natural killer cells (parental graft to F1 recipients). Ongoing studies have shown that antibody mediated lesions are dependent on NK cells, but not complement, the latter in contrast to the dependence on complement fixation in acute rejection.
Mechanisms of Graft Acceptance (human, monkey, pig, mice)
Dr. David Sachs, Ben Cosimi, Smith, Colvin and collaborators have published a series of studies on tolerance induction via mixed chimerism in non-human primates. The encouraging results have led to successful pilot clinical trials through the ITN, recently reported in the New England Journal of Medicine. Ongoing studies seek to identify the key cellular and molecular events that may distinguish the infiltrate in grafts in tolerant and non-tolerant recipients.
Robert B. Colvin, MD
Massachusetts General Hospital
Benjamin Castleman Distinguished Professor of Pathology
Harvard Medical School
Alessandro Alessandrini, PhD
R. Neal Smith, MD, PhD
Kazunobu Shinoda, MD
Ivy Rosales, MD
Evan Farkash, MD, PhD
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 Massachusetts General Hospital, which can detect cells labeled with fluorescent proteins and dyes.