title: Agonistic monoclonal antibody against CD40 receptor decreases lymphocyte apoptosis and improves survival in sepsis.
abstract: 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.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Schwulst
authors.forename: Mitchell H
authors.initials: MH
authors.lastname: Grayson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: DiPasco
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Davis
authors.forename: Tejal S
authors.initials: TS
authors.lastname: Brahmbhatt
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Ferguson
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hotchkiss
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use*; D017209:Apoptosis / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D002469:Cell Separation; D002470:Cell Survival / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D016131:Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010538:Peritonitis / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D018805:Sepsis / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens