T Cell–Monocyte Contact Enhances Tumor Necrosis Factor–α Production in Response toMycobacterium leprae

Abstract

Tumor necrosis factor (TNF)-alpha has been implicated as a key factor in inflammatory processes occurring in erythema nodosum leprosum (ENL). In the present study, the roles of soluble factors and contact-mediated interaction in the induction of enhanced TNF-alpha secretion in leprosy have been investigated. In vitro studies have demonstrated that Mycobacterium leprae per se is a poor stimulus for TNF-alpha production by purified monocytes obtained from normal subjects, although this could be enhanced by either exogenous interferon-gamma or cell contact with fixed activated T lymphocytes. Further investigations demonstrated that monocyte-T cell contact enhanced M. leprae-induced TNF-alpha production by peripheral blood mononuclear cells of ENL patients and was modulated by blocking antibodies to CD40L, CD69, and CD18. These results suggest that physical contact with T cells isolated from patients in a particular disease state (ENL) modulates monocyte function and may contribute to the secretion of proinflammatory cytokines described in ENL.

Enhancement ofMycobacterium tuberculosis-Induced Tumor Necrosis Factor Alpha Production from Primary Human Monocytes by an Activated T-Cell Membrane-Mediated Mechanism

“…These beta-integrins are involved both in intercellular adhesion and in phagocyte-M. tuberculosis binding, yet our preliminary attempts to block FAT stimulation with anti-CD11b and anti-CD18 antibodies achieved only partial inhibition of TNF-␣ secretion. These results were subsequently supported when neither anti-CD18, anti-CD40, nor anti-CD69 was able to completely abrogate FAT-stimulated TNF-␣ release from the monocytes of reactional leprosy patients (29). Antibody blocking of FAT-mediated stimulation with anti-CD69 or anti-CD2 has also achieved only partial inhibition (8,20,23), despite the ability of its immobilized ligand, CD58, to stimulate TNF secretion (51).…”

“…1 to 3). Several membrane-associated candidate molecules modify monokine release in other systems, including CD11a,b,c, CD18, CD40L, CD69, and CD2, yet none of these molecules appears to be acting in isolation upon human monocytes (8,14,23,29,35,47,51). For example, FAT with undetectable levels of CD40L are capable of stimulating monokine secretion (32), and ligation of monocyte CD11/ CD18 in the absence of costimulation produces no TNF-␣ (14,51).…”

A Systematic Review of Immunological Studies of Erythema Nodosum Leprosum

“…Interestingly, the studies that measured the ex vivo PBMC production of TNF-α in response to lipopolysaccharide, BCG, or M. leprae in patients with ENL as compared to BL/LL patients showed consistently greater amounts of TNF-α secretion in patients with ENL (150, 155–157). …”

Imunologia da hanseníase

“…6,[58][59][60] No entanto, os fatores precipitantes e mecanismos fisiopatoló-gicos envolvidos no desencadeamento de ambos os tipos de episódio reacional permanecem ainda mal definidos. 2,61 Evidências indicam que a RR associa-se a aumento abrupto da imunidade mediada por células, classicamente representada pela reação tipo IV de Gell & Coombs, sendo possivelmente desencadeada por reação aos antígenos bacilares fragmentados. Em geral observada em pacientes borderline após o início da terapêutica, a RR costuma ser mais precoce nos pacientes BT e BB, do que nos BV.…”

“…Contudo, ainda é considerado incerto o fato de a ação da talidomida sobre o ENH ser exclusivamente mediada pela inibição do TNF-α, pois também age co-estimulando a produção de IL-2 pelas células T. 62,68,70 Além disso, há relatos de tratamento eficaz do ENH com azatioprina, metotrexato, zinco oral e anticorpo monoclonal quimérico antiTNF, o infliximabe. 60 A compreensão dos inúmeros mecanismos que regem a indução e a manutenção dos episódios reacionais é também importante para facilitar o desenvolvimento de novas estratégias para prevenir ou tratar complicações desses processos inflamatórios, 61 que são universalmente reconhecidos como causadores de deformidades e incapacidades. 60 …”