Sign
out: Renal pathology.
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 20
research fellows have received training in this laboratory.
Acute and chronic antibody-mediated
rejection (human and monkey studies)
Dr. Colvin’s group found 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 category of acute antibody mediated rejection
has been incorporated into the Banff criteria and
has become the standard of care. At a 2003 NIH consensus
conference and the 2005 Banff Conference, a working
draft for chronic antibody mediated rejection proposed
by Dr. Colvin was accepted. Dr. Colvin’s group
provides the core pathology laboratory for a large
NIH funded multicenter trial group (Collaborative
Trials in Organ Transplantation) that will address
this question.
Pathogenesis of chronic allograft
vascular disease (murine studies)
A major problem in the long-term organ graft is the
development of a chronic arteriopathy, which has an
unknown pathogenesis. Dr. Paul Russell of the Transplantation
Unit and Dr. Colvin 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 knock out mice), T cells (male to female
grafts) or natural killer cells (parental graft to
F1 recipients). Dr. Colvin’s group showed that
C4d deposits in the myocardial capillaries of the
mouse after passive transfer of complement fixing
monoclonal anti-donor class I antibody and, with Drs.
Uehara and Cornell, is currently studying, the role
of complement fixation, Fc receptors and mechanisms
of accommodation in mouse kidney and heart grafts.
Induction of tolerance (human,
monkey, pig)
Dr. David Sachs, Ben Cosimi, 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 funded
clinical trials through the NIH Immune Tolerance
Network (ITN). Dr. Colvin’s
laboratory serves a national core facility for the
analysis of the protocol renal biopsies from these
trials. Ongoing studies seek to identify the key
cellular and molecular events (such as infiltration
by foxp3+ immunoregulatory cells) that may distinguish
the infiltrate in grafts in tolerant and non-tolerant
recipients.
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