Posted by Marina on June 01, 1999 at 17:36:16:
June 1999 Volume 5 Number 6 pp 686 - 693
Treatment with humanized
monoclonal antibody against
CD154 prevents acute renal
allograft rejection in nonhuman
primates
Allan D. Kirk1, 2, 3, Linda C. Burkly4, D. Scott Batty3,
Roxanne E. Baumgartner1, Justin D. Berning1, Kelvin
Buchanan1, John H. Fechner2, Rhonda L. Germond1,
Robert L. Kampen1, Noelle B. Patterson1, S. John
Swanson3, Douglas K. Tadaki1, Christopher N. TenHoor4,
Leonard White1, Stuart J. Knechtle2 & David M. Harlan1
CD154 is the ligand for the receptor CD40. This ligand–receptor pair
mediates endothelial and antigen-presenting cell activation, and
facilitates the interaction of these cells with T cells and platelets. We
demonstrate here that administration of a CD154-specific monoclonal
antibody (hu5C8) allows for renal allotransplantation in outbred,
MHC-mismatched rhesus monkeys without acute rejection. The effect
persisted for more than 10 months after therapy termination, and no
additional drug was required to achieve extended graft survival.
Indeed, the use of tacrolimus or chronic steroids seemed to
antagonize the anti-rejection effect. Monkeys treated with antibody
against CD154 remained healthy during and after therapy. The
mechanism of action does not require global depletion of T or B
cells. Long-term survivors lost their mixed lymphocyte reactivity in a
donor-specific manner, but still formed donor-specific antibody and
generated T cells that infiltrated the grafted organ without any
obvious effect on graft function. Thus, therapy with antibody against
CD154 is a promising agent for clinical use in human
allotransplantation.
1. The Naval Medical Research Center, Immune Cell Biology Program 8901
Wisconsin Avenue, Bethesda, Maryland 20889, USA
2. The Division of Transplantation, University of Wisconsin School of
Medicine, H4/710, 600 Highland Avenue, Madison, Wisconsin 53792, USA
3. The Organ Transplant Service, Walter Reed Army Medical Center, Ward
48, 6825 16th Street, NW, Washington, DC 20307, USA
4. Biogen, 14 Cambridge Center, Cambridge, Massachusetts 02142, USA
************************
Here's CNN's reference to the Nature Medicine article:
Strategy to Block Organ Rejection
Shows Promise in Monkey Studies
AP
01-JUN-99
NEW YORK (AP) -- Drugs designed to teach the body to accept transplanted
organs have remained effective for up to a year in monkeys that received kidneys,
according to researchers.
Scientists hope the experimental treatment will one day free some transplant
patients from having to take anti-rejection drugs for the rest of their lives. The
standard drugs suppress the immune system and leave patients vulnerable to
infections and tumors.
Researchers are planning studies of the experimental treatment in people, said Dr.
Allan Kirk of the Naval Medical Research Center in Bethesda, Md.
He and co-authors describe the monkey study in the June issue of the journal
Nature Medicine. Two years ago, Kirk and colleagues reported on a similar
treatment that staved off rejection for more than nine months in monkeys. The new
treatment includes only one of the two substances administered in the prior work.
The goal is to teach the immune system to accept the transplanted tissue rather
than attack it. To do that, researchers injected the monkeys with a protein to
prevent certain blood cells from delivering a "danger" signal to other cells, an initial
event in rejection.
The protein is called hu5C8. The researchers gave it to nine monkeys the morning
of the kidney transplant, just after the surgery, about once a week for four weeks
after that, and finally once a month for five months.
Eight of the nine treated monkeys remain alive and well with no organ rejection. Two
have lived about a year so far since the end of treatment, and another more than six
months. The ninth monkey died from an unrelated cause.
In a commentary accompanying the article, immune-system expert Polly Matzinger
of the National Institutes of Health said a 1996 study had shown the approach
works in mice. But transplant researchers largely overlooked that report, she said.
"Well," she wrote, "it is time to pay attention!"
Copyright 1999& The Associated Press. All rights reserved. This material may not be published,
broadcast, rewritten, or redistributed.
And here's Nature Medicine's Table of contents for the June issue.
Unfortunately, I can't access the entire article or even the pdf format because I'm not a (paid) subscriber.
Marina