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1.
Cancers (Basel) ; 13(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917839

RESUMO

Tumor necrosis factor (TNF) and lymphotoxin alpha (LTα) are two related cytokines from the TNF superfamily, yet they mediate their functions in soluble and membrane-bound forms via overlapping, as well as distinct, molecular pathways. Their genes are encoded within the major histocompatibility complex class III cluster in close proximity to each other. TNF is involved in host defense, maintenance of lymphoid tissues, regulation of cell death and survival, and antiviral and antibacterial responses. LTα, known for some time as TNFß, has pleiotropic functions including control of lymphoid tissue development and homeostasis cross talk between lymphocytes and their environment, as well as lymphoid tissue neogenesis with formation of lymphoid follicles outside the lymph nodes. Along with their homeostatic functions, deregulation of these two cytokines may be associated with initiation and progression of chronic inflammation, autoimmunity, and tumorigenesis. In this review, we summarize the current state of knowledge concerning TNF/LTα functions in tumor promotion and suppression, with the focus on the recently uncovered significance of host-microbiota interplay in cancer development that may explain some earlier controversial results.

2.
J Leukoc Biol ; 107(6): 933-939, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32040234

RESUMO

Systemic TNF neutralization can be used as a therapy for several autoimmune diseases. To evaluate the effects of cell type-restricted TNF blockade, we previously generated bispecific antibodies that can limit TNF secretion by myeloid cells (myeloid cell-specific TNF inhibitors or MYSTIs). In this study several such variable domain (VH) of a camelid heavy-chain only antibody-based TNF inhibitors were compared in relevant experimental models, both in vitro and in vivo. Pretreatment with MYSTI-2, containing the anti-F4/80 module, can restrict the release of human TNF (hTNF) from LPS-activated bone marrow-derived macrophage (BMDM) cultures of humanized TNF knock-in (mice; hTNFKI) more effectively than MYSTI-3, containing the anti-CD11b module. MYSTI-2 was also superior to MYSTI-3 in providing in vivo protection in acute toxicity model. Finally, MYSTI-2 was at least as effective as Infliximab in preventing collagen antibody-induced arthritis. This study demonstrates that a 33 kDa bispecific mini-antibody that specifically restricts TNF secretion by macrophages is efficient for amelioration of experimental arthritis.


Assuntos
Anticorpos Monoclonais/farmacologia , Artrite Experimental/terapia , Antígeno CD11b/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Cadeias Pesadas de Imunoglobulinas/farmacologia , Células Progenitoras Mieloides/efeitos dos fármacos , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Inibidores do Fator de Necrose Tumoral/farmacologia , Animais , Antirreumáticos/farmacologia , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/patologia , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/imunologia , Expressão Gênica , Humanos , Infliximab/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Transgênicos , Células Progenitoras Mieloides/imunologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
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