title: Alloreactive CD8 T-cell primed/memory responses and accelerated graft rejection in B-cell-deficient sensitized mice.
abstract: BACKGROUND
  The sensitized patients can develop an accelerated form of graft rejection mediated by humoral and T-cell-mediated responses, which are resistant to currently used immunosuppression.
  
  
  RESULTS
  In our model of fulminant cardiac allograft rejection in sensitized hosts, groups of wild-type (WT) and B-cell-deficient (BKO) mice (B6) were challenged with skin grafts (B/c). Alloreactive CD8 T effector (Teff) activation and T memory (Tmem) differentiation during a 60-day follow-up period were reduced in the absence of B-cell help. The expression of interleukin (IL)-2Rα, IL-7Rα, and IL-15Rα, which support/program CD8 Teff/Tmem expansion, differentiation, and survival, were selectively decreased in BKO hosts. Unlike in WT, in vivo cytotoxic activity analysis of alloreactive Tmem recall response has revealed decreased donor-type (B/c) but not third-party (C3H) cell lysis in sensitized BKO hosts. However, such impaired allo-Ag specific Tmem recall function was insufficient to markedly prolong cardiac allograft survival in sensitized BKO recipients. Indeed, despite quantitative and statistically significant differences between both animal groups, the biological impact of decreased CD8 Teff/Tmem activation and function in the sensitization phase was marginal. Indeed, cardiac allografts underwent fulminant rejection in sensitized BKO, albeit with somewhat delayed kinetics. Interestingly, unlike in naïve counterparts, the rejection cascade remained CD154 blockade-resistant, evidenced by comparable kinetics, and intra-graft cytokine gene profiles in MR1 monoclonal antibody-treated sensitized WT and BKO hosts.
  
  
  CONCLUSIONS
  Although B cells were important for optimal alloreactive CD8 Teff/Tmem function in the sensitization phase, the fulminant rejection of cardiac allografts was B-cell-independent, and CD154 blockade-resistant, as in WT hosts.
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Haofeng
authors.initials: H
authors.lastname: Ji
authors.forename: Xiu-Da
authors.initials: XD
authors.lastname: Shen
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhai
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007075:Immunoglobulin M / Q000172:deficiency / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000235:genetics / Q000378:metabolism; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000378:metabolism; D016038:Skin Transplantation / Q000276:immunology*; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D007075:Immunoglobulin M; D007148:Immunoglobulin mu-Chains; D018123:Receptors, Interleukin; D023201:CD40 Ligand