title: Anti-CD3 epsilon F(ab')2 fragments inhibit T cell expansion in vivo during graft-versus-host disease or the primary immune response to nominal antigen.
abstract: This study was undertaken to distinguish between several mechanisms responsible for graft-vs-host disease (GVHD) protection in anti-CD3epsilonF(ab')2 fragment (Fr)-treated recipients: TCR down-modulation, deletion, failure of expansion, or anergy induction. To quantify alloreactive T cell expansion and function, thoracic duct lymphocytes (TDL) were analyzed. Sixfold fewer donor TDL T cells were recoverable from anti-CD3epsilonF(ab')2 Fr as compared with irrelevant F(ab')2 Fr-treated recipients at the time of peak T cell expansion in vivo. Kinetic analysis revealed that donor T cell expansion was inhibited and not simply delayed by anti-CD3epsilonF(ab')2 Fr. Similar proportions of TDL T cells in irrelevant and anti-CD3epsilonF(ab')2 Fr were undergoing apoptosis. Although TCR modulation was observed, donor TDL T cells had intact anti-host alloresponses as compared with irrelevant F(ab')2 Fr-treated recipients. Because donor CD4+ T cells are primarily responsible for GVHD in this model, an adoptive transfer system was used in which the function and kinetics of expansion of OVA-specific CD4+ TCR transgenic cells could be physically tracked. Relevant Fr severely blunted CD4+ TCR transgenic T cell clonal expansion after OVA administration. Nonviable transgenic and nontransgenic T cells were proportionally similar in OVA-pulsed recipients, regardless of whether relevant or irrelevant F(ab')2 Fr were given. After discontinuing Fr, transgenic T cells were found to have intact in vitro OVA-specific responses. Our current and previous results suggest that reduced donor T cell expansion and T cell depletion both contribute to GVHD protection by anti-CD3epsilonF(ab')2 Fr. These data have implications for designing therapeutic approaches directed toward TCR targeting in humans.
authors.affiliation: Department of Pediatrics, University of Minnesota Hospital, Minneapolis 55455, USA. blaza001@maroon.tc.umn.edu
authors.forename: B R
authors.initials: BR
authors.lastname: Blazar
authors.forename: M K
authors.initials: MK
authors.lastname: Jenkins
authors.forename: P A
authors.initials: PA
authors.lastname: Taylor
authors.forename: J
authors.initials: J
authors.lastname: White
authors.forename: A
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: R
authors.initials: R
authors.lastname: Korngold
authors.forename: D A
authors.initials: DA
authors.lastname: Vallera
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage*; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D007399:Interphase / Q000276:immunology; D007519:Isoantigens / Q000276:immunology*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013897:Thoracic Duct / Q000166:cytology
chemical_list: D016207:Cytokines; D007140:Immunoglobulin Fab Fragments; D007166:Immunosuppressive Agents; D007519:Isoantigens; D017260:Receptor-CD3 Complex, Antigen, T-Cell