"Autoimmunity is enormously complex, with many causes," Jeffrey Ravetch, professor at Rockefeller University's laboratory of molecular genetics and immunology, told BioWorld Today. "But even though it's so complex, there are central gatekeepers. And affecting one of those may be enough to close the gates, if you will, and reverse the disease."
Data supporting the notion of such critical gatekeepers, and reporting the consequences of manipulating one of them, was published by Ravetch and his colleagues at Rockefeller University in New York City and St. Jude Children's Research Hospital in Memphis, Tenn., in the Jan. 28, 2005, issue of Science. The paper bears the title "Restoration of Tolerance in Lupus by Targeted Inhibitory Receptor Expression."
In contrast to the social sciences, in which tolerance means not attacking those who are different, in immunology the term is used to describe the immune system's ability to recognize and not attack self. Ravetch and his colleagues are interested in peripheral mechanisms to maintain tolerance.
There are two types of gatekeeper processes. Central mechanisms occur early in development and try to prevent autoimmune cells from entering the circulation. Late processes are both the cleanup crew for the failures of the early ones - corralling autoimmune cells that evade early central mechanisms and make it into circulation - and for ongoing vigilance to make sure that antigen exposure later in life does not lead to autoimmunity.
From a clinical development perspective, late gatekeepers are more promising because, as Ravetch noted, "that's what you have access to" and early stage processes are finished by a few months after birth. Another reason late processes also are potentially easier to access - and from there, manipulate - is that they are active in the periphery.
Ravetch and his colleagues focused on Fc receptors on B cells. Antibodies consist of two regions, an "infinitely varied" Fab portion that binds the antigen and an Fc portion, which is invariant, at least within an immunoglobulin class.
The Fc portion is the part of the antibody that determines the fate of the bound antibody-antigen complex.
"It tells the antibody what to do after binding has occurred," by directing it toward a specific type of effector cell, Ravetch said. B cells have both activating and inhibitory Fc receptors, which work in tandem to regulate their sensitivity to immunogens. Inhibitory Fc receptors, which down-regulate cellular responsiveness, are involved in maintaining immune system tolerance.
The scientists previously had identified a specific type of Fc receptor, the FC?RIIB receptor, which is critical for maintaining tolerance in mice. Mice lacking the receptor develop lupus-like symptoms, which lead to kidney problems and eventually kill them prematurely. In the studies reported in the Science paper, they developed a retroviral vector to reconstitute the RIIB receptor in bone marrow.
When irradiated mice were transplanted with autoimmune-prone bone marrow that had been transduced to reconstitute the RIIB receptor, they remained healthy, while mice receiving untransduced autoimmune-prone bone marrow soon developed the symptoms of lupus, suggesting the RIIB receptor is critical to maintaining tolerance under normal conditions.
To investigate the mechanisms underlying that protection, Ravetch and colleagues looked at the antibodies produced by both groups of mouse-transplant recipients. In autoimmune disease, mice (and humans) produce antibodies to many different structures, but "anti-DNA and antichromatin antibodies are most problematic, just because there is so much of it," Ravetch said. The antibody-antigen complexes usually are cleared by the kidneys, but when large amounts are produced, the kidneys cannot keep up with their trash disposal function, and deposits are formed that lead to kidney disease, the most serious consequence of lupus.
Mice transplanted with RIIB containing bone marrow had less anti-DNA and antichromatin antibodies, and showed no evidence of kidney disease in histological examination, while untreated or sham-treated mice showed "substantial renal pathology."
Using immunocytochemical methods, the scientists next investigated which cell types expressed the inhibitory RIIB receptor after transduction. They found that about 40 percent of B cells did so, making them the most likely candidates to mediate RIIBs beneficial effects, though small numbers of immature T cells and a few other cell types did express RIIB, as well.
Ravetch said he hopes his findings ultimately will be applicable in clinical settings, noting that "the goal of biomedical research is to impact human disease." He is collaborating with researchers from Columbia University who are testing their patients to see whether the same pathways are affected in humans as in mice. He called the initial results encouraging; a paper detailing the findings is under peer review.
While the gene-therapy approach used in the paper might eventually be a viable therapeutic approach in humans, Ravetch's group also is working on identifying small molecules that might be able to influence the balance of activation and inhibition in B cells. The group has no industrial collaborations, but Ravetch expects some in the future, as the science matures. He himself is a co-founder of Macrogenics Inc., a Rockville, Md.-based biotechnology company developing therapeutics that target activating Fc receptors.
But the work presented in the Science paper is unrelated to Macrogenics' area of interest, and the company didn't fund the research and isn't planning on licensing or otherwise commercializing it.