Title page for ETD etd-07022004-214740


Type of Document Dissertation
Author Tadesse Argaw, Azeb
URN etd-07022004-214740
Title A Study of the Anti-Inflammatory, Anti-Microbial and Immunomodulatory Properties of Thalidomide in Leprosy
Degree Doctor of Philosophy (Ph.D.)
Department Veterinary Microbiology & Parasitology (Veterinary Medical Sciences)
Advisory Committee
Advisor Name Title
E. J. Shannon Committee Chair
J. B. Malone Committee Member
J. E. Miller Committee Member
J. L. Krahenbuhl Committee Member
Nina Lam Dean's Representative
Keywords
  • thalidomide
  • mycobacterium leprae
  • erythema nodosum leprosum (ENL)
  • reversal reaction (RR)
Date of Defense 2004-06-23
Availability unrestricted
Abstract
During the course of their disease, leprosy patients may experience two types of inflammatory reactions- erythema nodosum leprosum (ENL) or reversal reaction (RR). Thalidomide is effective treatment for ENL, but not for RR. Using concentrations of thalidomide similar to that achieved in the treatment of ENL, we investigated thalidomide’s effect on reactions, viability of M. leprae, and integrity of plasma membranes.

Cells from patients with and without RR were stimulated with M. leprae (AFB), a cytosol fraction of M. leprae (MLSA) or DHAR (DHAR) antigen, and the effect of thalidomide on lymphocyte proliferation, expression of TNF-a mRNA and synthesis of TNF-a was investigated. Thalidomide enhanced MLSA and DHAR induced proliferation of cells from RR patients. The expression of TNF-a mRNA was variable, but thalidomide generally suppressed the synthesis of TNF-a. In a sub-set of RR patients, thalidomide enhanced AFB-induced cell proliferation, and the expression of TNF-a mRNA and TNF-a.

ENL has been described as a consequence of M. leprae antigens released from macrophages binding antibody and inducing inflammation. Thalidomide did not affect the viability of M. leprae residing in IFN-g/LPS activated mouse macrophages, nor did it suppress TNF-a or nitrite.

Drugs may be anti-inflammatory by stabilizing cell membranes. Thalidomide failed to protect the plasma membrane of neutrophils and THP-1 cells from osmotic lysis. Thalidomide stabilized the membrane of erythrocytes from plasma free blood, but not from whole blood. In vivo, the stability of erythrocytes membranes from subjects after ingestion of thalidomide was not affected.

In conclusion, thalidomide did not alter the viability of M. leprae, nor the integrity of the plasma membrane of inflammatory cells. It could enhance or suppress M. leprae antigen-induced synthesis of TNF-a. Interestingly, in 15 of 75 RR patients cells stimulated with AFB, thalidomide acted as a co-stimulant enhancing cell proliferation, synthesis of mRNA for TNF-a and TNF-a. Thalidomide’s enhancing effect on TNF-a in RR appears to be dependent on the stimulant and IL-2 signaling. As the inflammation in RR is associated with the emergence of antigen-reactive T-cells and TNF-a, we speculate that the use of thalidomide in the treatment of RR may exacerbate the reaction

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