Agonistic monoclonal antibody against CD40 receptor decreases lymphocyte apoptosis and improves survival in sepsis. J Immunol 2006 Jul 01;177(1):557-65
Date
06/21/2006Pubmed ID
16785553DOI
10.4049/jimmunol.177.1.557Scopus ID
2-s2.0-33745316012 (requires institutional sign-in at Scopus site) 44 CitationsAbstract
Sepsis causes a marked apoptosis-induced depletion of lymphocytes. The degree of lymphocyte apoptosis during sepsis strongly correlates with survival. CD40, a member of the TNFR family, is expressed on APCs and has potent antiapoptotic activity. In this study we determined whether an agonistic Ab against CD40 could protect lymphocytes from sepsis-induced apoptosis. Secondly, we examined potential antiapoptotic mechanisms of the putative protection. Lastly, we aimed to determine whether anti-CD40 treatment could improve survival in sepsis. CD1 mice were made septic by the cecal ligation and puncture method and treated postoperatively with anti-CD40 Ab. Treatment with anti-CD40 completely abrogated sepsis-induced splenic B cell death and, surprisingly, decreased splenic and thymic T cell death as well (p < 0.001). To investigate the mechanism of protection of anti-CD40 therapy on T cells, CD40 receptor expression was examined. As anticipated, the CD40 receptor was constitutively expressed on B cells, but, unexpectedly, splenic and thymic T cells were found to express CD40 receptor during sepsis. Furthermore, CD4+CD8- T cells were the predominant subtype of T cells expressing CD40 receptor during sepsis. Additionally, the antiapoptotic protein Bcl-x(L) was found to be markedly increased in splenic B and T cells as well as in thymic T cells after treatment with anti-CD40 Ab (p < 0.0025). Lastly, mice that were made septic in a double injury model of sepsis had improved survival after treatment with anti-CD40 as compared with controls (p = 0.05). In conclusion, anti-CD40 treatment increases Bcl-x(L), provides nearly complete protection against sepsis-induced lymphocyte apoptosis, and improves survival in sepsis.
Author List
Schwulst SJ, Grayson MH, DiPasco PJ, Davis CG, Brahmbhatt TS, Ferguson TA, Hotchkiss RSMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Monoclonal
Apoptosis
CD40 Antigens
Cell Separation
Cell Survival
Disease Models, Animal
Humans
Leukocytes, Mononuclear
Lymphocyte Subsets
Male
Mice
Mice, Inbred C57BL
Peritonitis
Sepsis
Spleen
T-Lymphocyte Subsets
Thymus Gland
Up-Regulation
