In Vitro Thalidomide Does Not Interfere With the Activation of Complement by M. leprae

March 2011 | Volume 10 | Issue 3 | Original Article | 274 | Copyright © 2011

Edward J. Shannon PhD, Felipe G. Sandoval BS, Melvyn J. Morales MS

National Hansen's Disease Programs, Laboratory Research Branch, Louisiana State University, Baton Rouge, LA

Abstract

Erythema nodosum leprosum (ENL) is an inflammatory reaction that may occur in multibacillary leprosy patients, and thalidomide is the treatment of choice. Its cause and the mechanism by which thalidomide suppresses ENL are not known. In the skin lesions, immune complexes and split products of complement are found. The activation of complement could precipitate ENL, and thalidomide could suppress the inflammation by inhibiting the activation of complement. To determine if thalidomide could suppress the activation of complement, we first incubated normal serum with thalidomide and with M. leprae or zymosan. The amount of residual functional complement was then assessed by determining the dilution of serum required to lyses sheep erythrocytes sensitized by rabbit antibodies (CH50 Assay). M. leprae and zymosan activated complement. The residual complement activity in the serum incubated with M. leprae or with zymosan was equivalent to that incubated with M. leprae or zymosan in the presence of thalidomide, hydrolyzed thalidomide and metabolites of thalidomide. Thalidomide did not inhibit the activation of complement by zymosan, a known initiator of complement activation by the alternative pathway, or by M. leprae. J Drugs Dermatol. 2011;10(3):274-278.

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INTRODUCTION

Erythema nodosum leprosum (ENL) is an inflammatory event that can occur in patients with multibacillary leprosy. In the skin lesions of ENL, immune complexes and split products of activated complement are found1,2along with numerous polymorphonuclear cells.3 The factor(s) that precipitate ENL are not known, and it is thought (by some) to be a manifestation of an immune complex mediated hypersensitivity reaction.

Hastings4 suggested that release of mycobacterium antigens from infected macrophages may be a factor that initiates ENL. The M. leprae antigen(s) may complex with specific antibodies or natural or cross-reactive antibodies initiating complement fixation by the classical pathway or the microbial debris may activate complement by the alternative pathway, or mannose-bindinglectin pathway. There is direct and indirect evidence to suggest that split products of activated complement are participants in the ENL reaction. Direct evidence was provided by Wemambu,5 who described deposits of immunoglobulin and complement in ENL lesions. Bjorvatn6 demonstrated significantly increased levels of C3b, a catabolic fragment of activated C3, in the plasma of 70 percent of patients with ENL but in only 18 percent of patients not in reaction. Saha7 suggested that complement activation during ENL most likely occurs by the alternative pathway. Sera from 20 patients with ENL were collected at the first visit, and four weeks after successful therapy with steroids. After assaying the 20 paired samples they found that the C3 level after remission of ENL rose, ranging from 13 to 22 percent during therapy. Serum levels of C1q and C4 did not alter significantly during ENL and also showed no difference in patients on ENL therapy.

When used under proper guidelines, thalidomide is the treatment of choice for ENL. Thalidomide is a drug that has anti- inflammatory properties which are especially evident in the treatment of ENL. Thalidomide could suppress ENL and prevent the egress of inflammatory polymorphonuclear cells into the lesions by inhibiting the activation of complement. Since the split products from activated complement can orchestrate immunological and inflammatory processes, we wanted to determine if thalidomide could suppress the activation of complement. To do this, we first incubated normal serum with M. leprae or with zymosan in the presence of thalidomide. The remaining residual functional C was then determined by defining the dilution of the serum required lyses 50 percent of the rabbit antibody sensitized sheep cells (CH'50 Titer or the CH50 Units).

METHODS AND MATERIALS

Thalidomide

Thalidomide, provided by Celgene Corporation (Summit, NJ), was dissolved in DMSO or aqueous solutions of 0.85% saline

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