Immunotherapy for Infectious Diseases

290 Wallis and Johnson
peripheral blood mononuclear cells (PBMCs) and alveolar macrophages (118,119).
Because of these properties, there has been considerable interest in exploring a possible
role for IL-12 immunotherapy in TB, balanced by concerns about its nonspecific
mechanism of action and potential toxicity. An early phase I trial of IL-12 immunotherapy
in TB is currently under way in the Gambia.
Thalidomide
Thalidomide, or �-N-phthalimidoglutarimide, is a synthetic derivative of glutamic
acid that was initially released as a sedative in Europe in 1957 but was withdrawn from
most countries 4 years later after recognition of its serious teratogenic effects, particularly
limb-shortening defects and phocomelia. The use of thalidomide as adjunctive therapy
in inflammatory and mycobacterial diseases has an interesting history. In 1965 an
Israeli dermatologist prescribed thalidomide as a sedative for six patients with lepromatous
leprosy and erythema nodosum leprosum (ENL) (120). ENL is a serious
reaction characterized by painful nodules, fever, malaise, wasting, vasculitis, and peripheral
neuritis that develops in 10–50% of patients treated for lepromatous leprosy. All six
patients treated with thalidomide improved within hours. This clinical observation
spurred a series of studies by other researchers to investigate its underlying mechanisms.
It is now recognized that thalidomide has complex antiinflammatory, immunologic,
and metabolic effects. Its activity has been attributed, at least in part, to its demonstrated
ability to inhibit TNF-� synthesis in vitro and in vivo (121,122). Thalidomide
also inhibits neutrophil phagocytosis, monocyte chemotaxis, and angiogenesis and, to
a lesser degree, inhibits lymphocyte proliferation to antigenic and mitogenic stimuli
(123–125). Thalidomide inhibits HIV-1 replication in the U-1 monocytoid cells and
PBMC from patients with advanced AIDS, primarily by inhibition of TNF-� (126,127).
These studies indicate potential clinical roles of thalidomide to limit TNF-related clinical
toxicities and to reduce cytokine-related HIV expression.
Thalidomide has subsequently been studied in several diseases in which immunologically
mediated mechanisms cause pathology. Thalidomide is effective for recurrent
oral, esophageal, and rectal apthous ulcers in patients with AIDS (128). It is also beneficial
in chronic graft-versus-host disease after bone marrow transplantation, discoid
lupus erythematosus, Behçet’s disease, and pyoderma gangrenosum and other inflammatory
skin diseases. Thalidomide also has modest activity in HIV wasting syndrome,
severe ulcerative colitis, microsporidial diarrhea, wasting in HIV-infected patients with
TB, and refractory M. avium complex infection in HIV-noninfected persons. Adjunctive
immunotherapy with thalidomide was studied in a double-blind placebo-controlled
trial of 39 HIV-infected adults with and without active TB (129). Patients with active
TB treated with thalidomide had decreased plasma TNF-� and HIV-1 viral levels and
greater weight gain than patients in the placebo group.
Thalidomide has also been evaluated as adjunctive therapy for TB meningitis, a relatively
common form of TB that often has serious sequelae. The severe inflammation
in the subarachnoid space is believed to play a central pathophysiologic role in the
cerebral edema, vasculitis, and infarction typically seen in this form of TB. Levels of
TNF-� and other inflammatory cytokines are increased in the cerebrospinal fluid in
patients with tuberculous meningitis and are correlated with disease progression and
brain injury in an animal model of tuberculous meningitis (130). Rabbits treated with