By David N. Leff
You don't have to acquire an HIV infection to become immunodeficient. All it takes to start your arsenal of immune defenses going downhill is normal aging.
Cellular immunologist David Hilbert puts it crisply: "There's a common senescence of the immune system that occurs in aged individuals." What this means is the gradual loss of the humoral B lymphocytes and cellular T lymphocytes that arm the body to fight off, or kill off, alien intruder pathogens - bacteria, viruses, parasites and fungi. Not to mention tumor cells, which to the immune system look a lot like foreigners.
B lymphocytes are white blood cells that patrol the body for such invading forces, which they attack by mustering up legions of antibodies, each of which has memorized its target enemy's name and serial number. T lymphocytes are a different formation of white cells, which send out battalions of killer cells to terminate pathogens with extreme prejudice.
The messengers that mobilize these combat units are cytokines, molecules that react to a threatening infection by recruiting large numbers of T cells and B cells for compulsory service. One such cytokine, interleukin-2 (IL-2), has gained some medical notoriety in recent years, notably for treating cancer. "IL-2 is a well-known growth factor for B cells," Hilbert observed. "It's also well known that it has serious side effects, which contributed to a lot of the toxicities seen in IL-2 clinical studies."
Hilbert is a section head in the department of cell biology at Human Genome Sciences Inc. (HGS) in Rockville, Md. He is co-discoverer of a new and different cytokine, called B lymphocyte stimulator (BLyS - pronounced "bliss"), which he describes as akin to IL-2, but without the drawbacks.
"BLyS," Hilbert told BioWorld Today, "is a growth factor that is produced as a protein on the surface of monocyte cells, and is then cleaved off to become a soluble cytokine. Unlike many other growth factors that have effects on B cells, such as IL-2, BLyS is far more specific."
BLyS-Full Mice Regained Missing Antibodies
He continued: "We have tested out the effect of this protein in mice, in which it induced increasing B-cell proliferation and antibody generation - which we would expect it to do. There were no serious side effects, such as have marked other cytokines used to enhance B-cell function.
"Another thing that's unique about BLyS," Hilbert went on, "is that the only cells that produce this protein are monocytes, precursors of immune-system macrophages. So we have both a very specific source and a very specific target for BLyS activity."
Hilbert is senior author of an article in the current issue of Science, dated July 9, 1999, which bears the title: "BLyS: Member of the tumor necrosis factor family and B lymphocyte stimulator."
"We didn't set out to find an immunological factor," he pointed out, "but rather to capture as many biological activities as we could. So the scope of what we did in terms of capturing immunological phenomena - as well as those that would affect various other organ systems - is what was novel about our approach."
The co-authors' approach points toward three distinct medical missions for the B-cell-galvanizing BLyS protein and its receptor, the HGS scientist suggested.
"The first would be to treat certain immune deficiency syndromes, such as organ-transplant recipients facing graft rejection by a misled immune system, and the B-cell-depleting effects of cancer chemotherapy. One specific use would be to quicken B-cell recovery in AIDS patients."
The second, Hilbert went on, "would use BLyS as a vaccine adjuvant. The whole concept in every aspect of BLyS revolves around its ability to enhance immunoglobulin antibody responses, by increasing the number of B cells that produce that antibody. So in any scenario where there's an immunocompromised individual or one who, for whatever other reason, can't respond to a vaccine - for example, vaccination programs that are only 20 percent efficient - if BLyS can raise that 20 to even 40 percent, it will have made a major contribution to that vaccine effort."
On this score, he continued, "Some of the flu vaccines given to aged people are only 20 percent effective. And in the hepatitis B vaccination program, I think 20 percent of its recipients respond poorly to that vaccine."
BLyS Antagonist Would Cool Too-Intense B Cells
The opposite side of that B-cell insufficiency coin is treating the diseases of its antibody overproduction - mainly leukemias and lymphomas. Here, Hilbert sees three potential forms of therapy.
"If a mutant form of that BLyS protein were to interact with its normal receptor, " he proposed, "it would prevent the normal BLyS from interacting.
"The second form of such a BLyS antagonist," he added, "is the one that most people classically think of, namely, an antibody to specifically inhibit the activity, bind BLyS and prevent it from interacting with its receptor. And then the third type of antagonist - it's theoretically possible - would be a soluble receptor. So you take the receptor that's normally found for BLyS and make a soluble form of it.
"Those three approaches," he observed, "have been used in many biotech scenarios. They are certainly three areas that HGS is very interested in - and I think we can't comment further at this point."
But the company's director of corporate communications and investor relations, Kathryn de Santis, added: "BLyS is one of the fast-track projects at HGS, and very likely to be our next IND application to FDA, early next year."
The director of NIH's National Institute of Allergy and Infectious Diseases (NIAID), immunologist Anthony Fauci, told BioWorld Today: "There are two aspects of the BLyS discovery that I like. It really is a validation of the concept of developing important, if not previously unknown, products by the genomics approach. Namely, to get a display of genes, and then express a particular product that might be of physiological importance - as opposed to doing it the other way. That is, when you have something that works, but don't know what it is, you get the genes for it, and then identify it.
"From a specific standpoint," Fauci added, "BLyS is very interesting because it's a molecule that's highly specific for B cells, and has the potential of being used ultimately for drugs to treat diseases that are characterized by abnormalities of B cell function."