RESUMO
BACKGROUND/AIM: Interleukin-2 (IL2) transgenic Ewing sarcoma cells reduce tumor growth in vivo and in vitro. In the present study we analyzed the expression of immune suppressive indoleamine-2,3-dioxygenase (IDO) in this model. MATERIALS AND METHODS: Expression of IDO was analyzed by polymerase chain reaction. The impact of the cluster of differentiation 137 (CD137)/CD137 ligand (CD137L) co-stimulatory system on expression of IDO and different cytokines was analyzed both in vivo and in vitro. RESULTS: Tumors that developed in vivo in the presence of IL2 transgenic tumor cells expressed IDO. The presence of CD137L transgenic tumor cells led to down-regulation of IDO. Further in-vitro analysis of this phenomenon indicated that IDO was expressed in tumor cells as a consequence of interferon-gamma produced by lymphocytes in response to IL2. Depending on the concentration of IL2, stimulation of CD137 increased or reduced cytokine production in lymphocytes. CONCLUSION: Our data indicate that the CD137/CD137L pathway can modulate the immune response against Ewing sarcoma cells.
Assuntos
Neoplasias Ósseas/terapia , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interferon gama/farmacologia , Interleucina-2/fisiologia , Sarcoma de Ewing/terapia , Animais , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/imunologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Linfócitos/enzimologia , Linfócitos/imunologia , Linfócitos/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Ligante OX40/genética , Ligante OX40/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma de Ewing/enzimologia , Sarcoma de Ewing/imunologia , Células Tumorais Cultivadas , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The beta-chains of HLA-DR molecules associated with susceptibility to rheumatoid arthritis (RA) share a common amino acid sequence in their third hypervariable region at position 70-74. This shared epitope could either contribute to preferential binding of a given disease-associated peptide, be involved in disease-induction by molecular mimicry or, by binding to heat shock proteins, influence antigen presentation. It is known that the Escherichia coli M(r)70,000 heat shock protein DnaK can bind peptides from the shared epitope. Using a highly sensitive method, we show that peptides covering the third hypervariable region of associated, but also most of the non-associated HLA-DR alleles, bind to DnaK. Similar binding specificities could be found for the constitutively expressed mammalian M(r)70,000 heat shock protein Hsc73 and the inducible mammalian Hsp72. However, peptides containing the amino acid sequence DERAA, found in HLA-DR alleles and strongly associated with protection from RA, did not bind any HSP70. Thus, our results suggest a possible association of non-binding of HSP70 to HLA-DR molecules or its 70-74 fragments and protection from RA.
