Nine out of every 10 people with tuberculosis live in the Third World.

Take the Republic of Uganda, for example. That Wyoming-size East African country's 20 million inhabitants have a life expectancy at birth of 40 years for males, 41 for females. Among those of its people who are infected with the AIDS virus, fully half are also actively infected with the TB germ, Mycobacterium tuberculosis. And of those adults who are HIV-negative, 10 to 20 percent have active TB.

Tuberculosis immunologist Christina Hirsch, at Case Western University, in Cleveland, travels often to Uganda in pursuit of the treacherous mycobacterium.

Her mission, Hirsch told BioWorld Today, is "mainly conducting descriptive studies to evaluate in more depth the immune function of people who are predominantly infected with TB, and of individuals who have both TB and HIV."

Hirsch is both a TB clinician and a bench immunologist. The current Proceedings of the National Academy of Sciences (PNAS), dated April 14, 1997, carries a paper of which she is lead author. Its title: "In vitro restoration of T cell responses in tuberculosis and augmentation of monocyte effector function against Mycobacterium tuberculosis by natural inhibitors of transforming growth factor ß [TGF- ß]."

Two-Faced TGF-ß Foils Anti-TB Antibiotics

What with more and more strains of M. tuberculosis becoming resistant to TB-directed antibiotics, Hirsch's strategy is to toughen up the body's own immune defense system as a crutch or shield to bolster antibiotics against that resistance.

"We can kill 80 to 90 percent of the non-resistant bacteria," she said, "but some few of the resistant ones stay alive.

"What ultimately happens to people who are resistant to two or more of these drugs," she pointed out, "is that we can do just so much for them. A lot of the time we treat, and then the disease is quiet for a short time, then flares up again, because one can never manage to wipe out all the multiple-resistant mycobacteria that are residing in the body."

In their end-run effort to reinforce the body's immune system, the Case Western group's research is focusing on a strange and sinister molecule called transforming growth factor beta (TGF-ß.)

"In normal, healthy people," Hirsch observed, "there is little or no TGF-ß." Apparently, this not-well-understood, multipurpose cytokine kicks in mainly in response to tissue damage, or to reinvigorate a flagging immune system's macrophages and T cells.

Macrophages, ironically, are cells derived from the immune system's monocytes to gobble up and spit out waste and debris, including mycobacteria -- which hole up inside those very macrophages. T cells, on the other hand, are equipped to seek out, identify and destroy invading pathogens.

Like a foreign intelligence service "turning" a captured enemy agent into a mole, M. tuberculosis subverts its victim's TGF-ß to its own purposes, by making the macrophage over-produce the growth factor.

"We don't exactly know what causes this excess," Hirsch allowed. To confirm the phenomenon, she and her colleagues had previously taken blood from patients with TB in Pakistan, plus healthy household contacts as controls, and grew up their white cells in tissue culture.

Then they stimulated these with PPD -- the purified protein derivative of the bacterium -- in the presence of antibodies specific for TGF-ß. This process normally reconstitutes a patient's T cell proliferation to levels of healthy contacts.

Production of interferon-gamma [INF-*] yielded similar T cell restoration.

"Interferon," Hirsch observed, "is probably the predominant cytokine that leads to control of TB infection, particularly activation of macrophages that can kill mycobacteria inside those cells."

Direct evidence, presumably linking TGF-ß to pulmonary TB, is a separate finding by the senior author of the PNAS paper, immunologist Zahra Toossi. She reported discovering TGF-ß expressed in granulomas (inflammatory particles) in the lungs of TB patients.

Newly Discovered Inhibitors Foil TGF-ß

Given their bill of particulars, indicting excessive TGF-ß of complicity in M. tuberculosis' attack on its victims' immunity, Hirsch and her co-authors set about finding ways of cutting that rogue growth factor down to size. As reported in their paper, they came up with two candidate inhibitors, decorin and latency-associated peptide, LAP for short.

Paradoxically, LAP itself is a piece of the TGF-ß action.

"It's quite peculiar," Hirsch observed. "TGF-ß is made from cells as a big precursor molecule, which contains both LAP and the active growth factor itself. After this LAP gets separated from the active part of that molecule, the TGF-ß can interact with its receptor and exert its biological effect."

She continued: "Once the LAP gets split off, there is also a possibility that it may reassociate, and thus negate the effects of the active factor."

If it does so, this reassembly corrects depressed T cell proliferation to levels enjoyed by healthy control individuals. The group found a similar T cell resurrection, performed by a proteoglycan molecule named decorin, which normally occurs in cartilage.

"Decorin actually binds to the core substance of TGF-ß," Hirsch observed, "and can abrogate -- at least in vitro -- some of its deleterious effects.

"I'm not sure," she continued, "whether at this point either of these TGF-inhibitors, decorin or LAP, offers much therapeutic advantage to the general population."

Her group is now "in the process of planning to look at the efficacy of these inhibitors in a mouse model." *