X-Message-Number: 31600
Date: Fri, 10 Apr 2009 09:18:43 -0700 (PDT)
From: 
Subject: Major Breakthrough In Transplantation Immunity


[Cryonics research is partly an offshoot of research into cryopreserving 
transplanation organs. If the research discussed below regarding the induction 
of tolerance to transplantation grafts pans out, this could greatly increase the
number of successful transplants that occur. I speculate that a consequent 
increase in transplant demand would in turn increase funding for organ 
cryopreservation, which would in turn indirectly benefit cryonics.]


Major Breakthrough In Transplantation Immunity

ScienceDaily (Apr. 9, 2009) - Australian scientists have made a discovery that 
may one day remove the need for a lifetime of toxic immunosuppressive drugs 
after organ transplants.


Professor Jonathan Sprent and Dr Kylie Webster from Sydney's Garvan Institute of
Medical Research, in collaboration with colleagues, Dr Shane Grey and Stacey 
Walters, have successfully tested a method, in experimental mice, of adjusting 
the immune system for just long enough to receive a tissue transplant and accept
it as 'self'. At no stage, during or after the procedure, is there any need for
immunosuppressive drugs.

"Under normal circumstances, the body would attack a transplanted organ unless 
immunosuppressive drugs such as cyclosporin were given," said Sprent. "In this 
project, mice were given a substance, or 'complex', that altered their immune 
systems, so that they accepted transplanted cells as their own."

Sprent developed the 'complex' with Professor Charles Surh from California's 
Scripps Research Institute and Dr Onur Boyman, physician and Head of the Basic 
Immunology Unit at the University Hospital of Lausanne in Switzerland.

The complex combines a molecule, interleukin-2 (IL-2), with an antibody in order
to stimulate immune cells known as T regulatory cells.

"In broad terms, IL-2 is a growth factor for T cells," explained Sprent. "My 
colleague Onur Boyman discovered that by combining IL-2 with different 
antibodies you can control its action, boosting specific populations of T cells,
while subduing others. For this project we needed to boost the numbers of T 
regulatory cells."

"T regulatory cells quiet the immune system, subduing the body's killer T cells 
when it's time to stop fighting an infection."

"The other side of the coin is that a superabundance of T regulatory cells 
prevents killer T cells from functioning. And you wouldn't want to be without 
killer T cells for long because they fight infections and cancers."

"For this project, we boosted T regulatory cells temporarily, in a procedure 
that we believe might be very useful clinically, particularly for preventing 
rejection."

It was the task of postdoctoral researcher Kylie Webster, working with Stacey 
Walters, to see if she could make the T regulatory cell response work in a 
clinically realistic setting.

"We took normal, healthy mice, injected them for three consecutive days with the
complex, then transplanted insulin-producing cells on the fourth day," said 
Kylie. "By the time of transplant there were huge numbers of T regulatory cells 
in their systems, making graft-destroying T cells ineffective."

"The numbers of T regulatory cells dropped over time, and the immune systems 
returned to normal in about two weeks. By that time 80% of the mice had accepted
the grafts of insulin producing cells as their own."

"This acceptance rate is very high for transplantation, with mice normally 
rejecting grafts within 2-3 weeks."

"A graft is considered accepted if it's tolerated after 100 days. We took some 
mice out to 200-300 days, and not one of them rejected."
While cautious, Professor Sprent is very encouraged by the results.

"We have yet to determine exactly how the complex works. Once we do, I believe a
clinical trial of this very non-toxic agent would be worthwhile."

"Our approach works well with pancreatic islets, or insulin-producing cells, but
we have yet to try other clinically-relevant grafts such as kidneys and hearts,
which are technically very difficult in mice," he said.

"I am also aware that effective approaches in mice do not necessarily give good 
results in humans because of subtle differences in the immune systems of mouse 
and man."

"Those provisos given, if we were able to duplicate this experiment in humans, 
it would fulfil the dream of everyone in the transplant field."

The results are now online in the current edition of Journal of Experimental 
Medicine.

Adapted from materials provided by Garvan Institute of Medical Research.

____________________________________________________________
Published online March 30, 2009
doi:10.1084/jem.20082824
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
C 2009 Webster et al.
This Article

BRIEF DEFINITIVE REPORT


In vivo expansion of T reg cells with IL-2-mAb complexes: induction of 
resistance to EAE and long-term acceptance of islet allografts without 
immunosuppression


Kylie E. Webster1, Stacey Walters1, Rachel E. Kohler1, Tomas Mrkvan1, Onur 
Boyman2, Charles D. Surh3, Shane T. Grey1, and Jonathan Sprent1

1 Immunology and Inflammation Division, Garvan Institute of Medical Research, 
Darlinghurst, NSW 2010, Australia

2 Division of Immunology and Allergy, University Hospital of Lausanne, 1011 
Lausanne, Switzerland
3 The Scripps Research Institute, La Jolla, CA 92037


Via a transcription factor, Foxp3, immunoregulatory CD4+CD25+ T cells (T reg 
cells) play an important role in suppressing the function of other T cells. 
Adoptively transferring high numbers of T reg cells can reduce the intensity of 
the immune response, thereby providing an attractive prospect for inducing 
tolerance. Extending our previous findings, we describe an in vivo approach for 
inducing rapid expansion of T reg cells by injecting mice with interleukin 
(IL)-2 mixed with a particular IL-2 monoclonal antibody (mAb). Injection of 
these IL-2-IL-2 mAb complexes for a short period of 3 d induces a marked 
(>10-fold) increase in T reg cell numbers in many organs, including the liver 
and gut as well as the spleen and lymph nodes, and a modest increase in the 
thymus. The expanded T reg cells survive for 1-2 wk and are highly activated and
display superior suppressive function. Pretreating with the IL-2-IL-2 mAb 
complexes renders the mice resistant to induction of experimental autoimmune 
encephalomyelitis; combined with rapamycin, the complexes can also be used to 
treat ongoing disease. In addition, pretreating mice with the complexes induces 
tolerance to fully major histocompatibility complex-incompatible pancreatic 
islets in the absence of immunosuppression. Tolerance is robust and the majority
of grafts are accepted indefinitely. The approach described for T reg cell 
expansion has clinical potential for treating autoimmune disease and promoting 
organ transplantation

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