Methods used by the body to selectively suppress the immune response may help make organ transplants safer and more effective, according to scientists.
"If you like, what we are trying to do is make every tissue transplant much more like a foetus," said Dr. Andrew L. Mellor, director of the Medical College of Georgia Immunotherapy Center and Georgia Research Alliance Eminent Scholar in Molecular Immunogenetics.
He’s referencing how the genetically different foetus, which should be attacked by the mother’s immune system, escapes by using powerful immune suppressors such as the enzyme indoleomine 2,3-dioxygenase. The lungs, liver, gut and eyes are examples of other human tissues that make use of this type of selective immune suppression to deal with routine contact with foreign, albeit usually harmless substances.
A new $1 million, three-year grant from Atlanta-based Carlos and Marguerite Mason Trust, administered by Wachovia Nonprofit and Philanthropic Services, will fund pre-clinical research exploring the most effective method for increasing IDO levels to improve transplant survival. The grant also will help explore the role of HLA-G dimer, another powerful immune modulator, in transplant survival and look for biomarkers that would give physicians a heads up that a rejection episode is mounting.
Using the model of a mouse with a skin graft, Dr. Phillip Chandler, a transplant biologist in Dr. Mellor’s lab, will use IDO stimulators before, during and after a transplant. They’ll also use IDO inhibitors to further define IDO’s role in graft survival. "That is how we will learn if IDO can be induced and if that expression protects transplants," Dr. Mellor said. "This is proof of concept we are talking about which gets us toward the clinic."
Current immunosuppressive therapies for transplant patients cause a generalised suppression of the immune response that puts them at increased risk for cancers and infections. Long-term IDO therapy could do that as well: "That is part of the experiment we still need to look at," Dr. Mellor said. However it also may be that short-term IDO inducer therapy will enable long-term graft survival. "It may get it through that window of difficulty."
The team also will explore the more localised approach used by foetuses and tumours, where specific tissue puts up a sort of immune barrier by expressing IDO. They’ll use a powerful viral vector as a vehicle to deliver the IDO gene directly into the tissue to be transplanted, turning the cells into "IDO over-expressers," Dr. Mellor said.
The vector was developed with the help of Georgia Research Alliance funding and Dr. Yukai He, a member of the MCG Cancer Center’s Immunotherapy Program and GRA Distinguished Investigator who specialises in cancer vaccine development.
"We have to try both directions: putting the IDO gene in locally or giving it systemically. We know the mechanism works in principle: that IDO is a good way to protect transplants. But we don’t know what is the most effective way," Dr. Mellor said.
Mason Trust funds also will enable expansion of studies in human samples by Dr. Anatolij Horuzsko, an immunologist in the MCG Center for Molecular Chaperone/Radiobiology and Cancer Virology, and Dr. Laura Mulloy, chief of the Section of Nephrology, Hypertension and Transplantation Medicine in the School of Medicine.
Several forms of HLA-G are effective at inhibiting the immune response – similar to the way foetuses and tumours use IDO – but Dr. Horuzsko has shown the dimer version – comprised of two chemically attracted monomers or molecules – is the best HLA-G at blocking transplant rejection in a mouse with a skin graft.
He already has measured HLA-G dimer levels in the blood of more than 50 kidney transplant patients and found pretty much what he’s seen in his animal studies: those who don’t reject their new kidneys have higher levels of HLA-G dimer. Now they’ll look at more patients to see if the finding holds true and look at IDO levels as well to see how they correlate with transplant success.
They’ll also look for novel biomarkers of transplant rejection. An Austrian group already has documented increased IDO activity as a prelude to a rejection episode, said Dr. Mellor, noting that in this scenario IDO could be rallying like fire-fighters to battle rejection. "It’s a potential early marker of a problem that transplant physicians will want to deal with," he said, noting that IDO’s role may differ in immediate acute rejections and more chronic rejection episodes.
By the end of three-year grant, MCG researchers in collaboration with Dr. Alan D. Kirk, scientific director of the Emory Transplant Center and GRA Eminent Scholar in Transplantation Immunology, want to move to the next step: to see if IDO can protect kidney transplants in non-human primates. If the promised potential holds up, the following step would involve transplant patients at MCG and Emory.
An MCG research team led by Drs. Mellor and David Munn found a decade ago that IDO was a primary mechanism for localised immune tolerance. Since then, they have explored the potential of increasing IDO expression to combat autoimmune disease such as type 1 diabetes and help transplanted organs survive and, conversely, turning IDO off to help kill tumours and attack infections such as HIV. Drs. Mellor and Munn co-direct a new Immuno Discovery Institute in the MCG School of Medicine which will help strengthen this type of translational science.
(Source: Medical College of Georgia: December 2008)