Thalidomide stimulates T cell responses and interleukin 12 production in HIV-infected patients.
We performed a placebo-controlled study to evaluate the effects of immunomodulatory treatment with thalidomide on HIV levels, TNF-alpha levels, and immune status of 31 HIV-infected individuals, after temporary suppression of viral replication with antiretroviral drugs. Treatment with a combination of zidovudine and lamivudine (ZDV/LMV) for 14 days resulted in a median decline in plasma viremia of 1.94 log10 RNA equivalents/ml. After discontinuation of ZDV/LMV, thalidomide therapy (200 mg/day for 4 weeks) did not retard the prompt return of HIV titers to the pretreatment levels, and had no effect on plasma levels of TNF-alpha. In contrast, thalidomide treatment resulted in significant immune stimulation. We observed increased levels of plasma soluble IL-2 receptor, soluble CD8 antigen, and IL-12 (p < 0.01 for all parameters), as well as increased cutaneous delayed-type hypersensitivity reactions to recall antigens (p < 0.01) in thalidomide-treated patients. These changes were associated with a median increase in HIV titer of 0.2 log10 RNA equivalents/ml in the thalidomide-treated group (p < 0.05), which resolved after stopping the drug. Further studies were performed in vitro to elucidate the mechanism of thalidomide-induced immune stimulation. When purified T cells from HIV-infected individuals were stimulated by immobilized anti-CD3 in the presence of thalidomide, a costimulatory effect of the drug was observed, resulting in increased production of IL-2 and IFN-gamma, and increased T cell-proliferative responses. Further experiments showed that thalidomide increased IL-12 production by antigen-presenting cells in a T cell-dependent manner. Our findings suggest a potential application for thalidomide as a novel immune adjuvant in HIV disease.
Haslett
P A
PA
The Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York 10021, USA. hasletp@rockvax.rockefeller.edu
Klausner
J D
JD
Makonkawkeyoon
S
S
Moreira
A
A
Metatratip
P
P
Boyle
B
B
Kunachiwa
W
W
Maneekarn
N
N
Vongchan
P
P
Corral
L G
LG
Elbeik
T
T
Shen
Z
Z
Kaplan
G
G
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D006968:Hypersensitivity, Delayed; D007376:Interleukin-2 / Q000096:biosynthesis*; D019259:Lamivudine / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013792:Thalidomide / Q000627:therapeutic use*; D019562:Viral Load; D015215:Zidovudine / Q000627:therapeutic use
D019380:Anti-HIV Agents; D016207:Cytokines; D007376:Interleukin-2; D019259:Lamivudine; D015215:Zidovudine; D013792:Thalidomide