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Molecular Medicine logoLink to Molecular Medicine
. 1995 May;1(4):384–397.

Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis.

J M Tramontana 1, U Utaipat 1, A Molloy 1, P Akarasewi 1, M Burroughs 1, S Makonkawkeyoon 1, B Johnson 1, J D Klausner 1, W Rom 1, G Kaplan 1
PMCID: PMC2229989  PMID: 8521296

Abstract

BACKGROUND: The monocyte-derived cytokine, tumor necrosis factor alpha (TNF alpha), is essential for host immunity, but overproduction of this cytokine may have serious pathologic consequences. Excess TNF alpha produced in pulmonary tuberculosis may cause fevers, weakness, night sweats, necrosis, and progressive weight loss. Thalidomide (alpha-N-phthalimidoglutarimide) has recently been shown to suppress TNF alpha production by human monocytes in vitro and to reduce serum TNF alpha in leprosy patients. We have therefore conducted a two-part placebo-controlled pilot study of thalidomide in patients with active tuberculosis to determine its effects on clinical response, immune reactivity, TNF alpha levels, and weight. MATERIALS AND METHODS: 30 male patients with active tuberculosis, either human immunodeficiency virus type 1 positive (HIV-1+) or HIV-1-, received thalidomide or placebo for single or multiple 14 day cycles. Toxicity of the study drug, delayed type hypersensitivity (DTH), cytokine production, and weight gain were evaluated. RESULTS: Thalidomide treatment was well tolerated, without serious adverse events. The drug did not adversely affect the DTH response to purified protein derivative (PPD), total leukocyte, or differential cell counts. TNF alpha production was significantly reduced during thalidomide treatment while interferon-gamma (IFN gamma) production was enhanced. Daily administration of thalidomide resulted in a significant enhancement of weight gain. CONCLUSIONS: The results indicate that thalidomide is well tolerated by patients receiving anti-tuberculosis therapy. Thalidomide treatment reduces TNF alpha production both in vivo and in vitro and is associated with an accelerated weight gain during the study period.

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Selected References

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  1. Aukrust P., Liabakk N. B., Müller F., Lien E., Espevik T., Frøland S. S. Serum levels of tumor necrosis factor-alpha (TNF alpha) and soluble TNF receptors in human immunodeficiency virus type 1 infection--correlations to clinical, immunologic, and virologic parameters. J Infect Dis. 1994 Feb;169(2):420–424. doi: 10.1093/infdis/169.2.420. [DOI] [PubMed] [Google Scholar]
  2. Barnes P. F., Fong S. J., Brennan P. J., Twomey P. E., Mazumder A., Modlin R. L. Local production of tumor necrosis factor and IFN-gamma in tuberculous pleuritis. J Immunol. 1990 Jul 1;145(1):149–154. [PubMed] [Google Scholar]
  3. Beutler B., Cerami A. The biology of cachectin/TNF--a primary mediator of the host response. Annu Rev Immunol. 1989;7:625–655. doi: 10.1146/annurev.iy.07.040189.003205. [DOI] [PubMed] [Google Scholar]
  4. Havell E. A. Evidence that tumor necrosis factor has an important role in antibacterial resistance. J Immunol. 1989 Nov 1;143(9):2894–2899. [PubMed] [Google Scholar]
  5. Johnson B. J., McMurray D. N. Cytokine gene expression by cultures of human lymphocytes with autologous Mycobacterium tuberculosis-infected monocytes. Infect Immun. 1994 Apr;62(4):1444–1450. doi: 10.1128/iai.62.4.1444-1450.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Kindler V., Sappino A. P., Grau G. E., Piguet P. F., Vassalli P. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989 Mar 10;56(5):731–740. doi: 10.1016/0092-8674(89)90676-4. [DOI] [PubMed] [Google Scholar]
  7. Makonkawkeyoon S., Limson-Pobre R. N., Moreira A. L., Schauf V., Kaplan G. Thalidomide inhibits the replication of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5974–5978. doi: 10.1073/pnas.90.13.5974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Moreira A. L., Sampaio E. P., Zmuidzinas A., Frindt P., Smith K. A., Kaplan G. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med. 1993 Jun 1;177(6):1675–1680. doi: 10.1084/jem.177.6.1675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. North R. J., Izzo A. A. Granuloma formation in severe combined immunodeficient (SCID) mice in response to progressive BCG infection. Tendency not to form granulomas in the lung is associated with faster bacterial growth in this organ. Am J Pathol. 1993 Jun;142(6):1959–1966. [PMC free article] [PubMed] [Google Scholar]
  10. Ogawa T., Uchida H., Kusumoto Y., Mori Y., Yamamura Y., Hamada S. Increase in tumor necrosis factor alpha- and interleukin-6-secreting cells in peripheral blood mononuclear cells from subjects infected with Mycobacterium tuberculosis. Infect Immun. 1991 Sep;59(9):3021–3025. doi: 10.1128/iai.59.9.3021-3025.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Sampaio E. P., Kaplan G., Miranda A., Nery J. A., Miguel C. P., Viana S. M., Sarno E. N. The influence of thalidomide on the clinical and immunologic manifestation of erythema nodosum leprosum. J Infect Dis. 1993 Aug;168(2):408–414. doi: 10.1093/infdis/168.2.408. [DOI] [PubMed] [Google Scholar]
  12. Sampaio E. P., Sarno E. N., Galilly R., Cohn Z. A., Kaplan G. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med. 1991 Mar 1;173(3):699–703. doi: 10.1084/jem.173.3.699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Sarno E. N., Grau G. E., Vieira L. M., Nery J. A. Serum levels of tumour necrosis factor-alpha and interleukin-1 beta during leprosy reactional states. Clin Exp Immunol. 1991 Apr;84(1):103–108. [PMC free article] [PubMed] [Google Scholar]
  14. Takashima T., Ueta C., Tsuyuguchi I., Kishimoto S. Production of tumor necrosis factor alpha by monocytes from patients with pulmonary tuberculosis. Infect Immun. 1990 Oct;58(10):3286–3292. doi: 10.1128/iai.58.10.3286-3292.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Valone S. E., Rich E. A., Wallis R. S., Ellner J. J. Expression of tumor necrosis factor in vitro by human mononuclear phagocytes stimulated with whole Mycobacterium bovis BCG and mycobacterial antigens. Infect Immun. 1988 Dec;56(12):3313–3315. doi: 10.1128/iai.56.12.3313-3315.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. van der Poll T., Jansen J., van Leenen D., von der Möhlen M., Levi M., ten Cate H., Gallati H., ten Cate J. W., van Deventer S. J. Release of soluble receptors for tumor necrosis factor in clinical sepsis and experimental endotoxemia. J Infect Dis. 1993 Oct;168(4):955–960. doi: 10.1093/infdis/168.4.955. [DOI] [PubMed] [Google Scholar]

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