title: mTOR Inhibition Suppresses Posttransplant Alloantibody Production Through Direct Inhibition of Alloprimed B Cells and Sparing of CD8+ Antibody-Suppressing T cells.
abstract: BACKGROUND
  De novo alloantibodies (donor-specific antibody) contribute to antibody-mediated rejection and poor long-term graft survival. Because the development of donor-specific antibody is associated with early graft loss of cell transplants and reduced long-term survival of solid organ transplants, we hypothesized that conventional immunosuppressives, calcineurin inhibitors (CNi), and mammalian target of rapamycin inhibitors (mTORi), may not be as effective for suppression of humoral alloimmunity as for cell-mediated immunity.
  
  
  METHODS
  Wild-type or CD8-depleted mice were transplanted with allogeneic hepatocytes. Recipients were treated with mTORi and/or CNi and serially monitored for alloantibody and graft survival. The direct effect of mTORi and CNi on alloprimed B cell function was investigated in Rag1 mice adoptively transferred with alloprimed IgG1 B cells. The efficacy of mTORi and/or CNi to suppress CD8-mediated cytotoxicity of IgG1 B cells was evaluated in in vitro and in vivo cytotoxicity assays.
  
  
  RESULTS
  Mammalian target of rapamycin inhibitors, but not CNi, reduced alloantibody production in transplant recipients, directly suppressed alloantibody production by alloprimed IgG1 B cells and delayed graft rejection in both low and high alloantibody producers. Combination treatment with mTORi and CNi resulted in loss of the inhibitory effect observed for mTORi monotherapy in part due to CNi suppression of CD8 T cells which downregulate alloantibody production (CD8 TAb-supp cells).
  
  
  CONCLUSIONS
  Our data support that mTORi is a potent inhibitor of humoral immunity through suppression of alloprimed B cells and preservation of CD8 TAb-supp cells. In contrast, alloantibody is readily detected in CNi-treated recipients because CNi does not suppress alloprimed B cells and interferes with downregulatory CD8 TAb-supp cells.
authors.affiliation: 1 Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH. 2 Center for Biostatistics, The Ohio State University, Columbus, OH.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Avila
authors.forename: Jason M
authors.initials: JM
authors.lastname: Zimmerer
authors.forename: Steven M
authors.initials: SM
authors.lastname: Elzein
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Pham
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Abdel-Rasoul
authors.forename: Ginny L
authors.initials: GL
authors.lastname: Bumgardner
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015536:Down-Regulation; D005838:Genotype; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D022781:Hepatocytes / Q000276:immunology / Q000637:transplantation*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007111:Immunity, Cellular / Q000187:drug effects; D056724:Immunity, Humoral / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007518:Isoantibodies / Q000097:blood / Q000276:immunology*; D016031:Liver Transplantation / Q000009:adverse effects / Q000379:methods; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
chemical_list: D016827:CD8 Antigens; D065095:Calcineurin Inhibitors; D018398:Homeodomain Proteins; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D047428:Protein Kinase Inhibitors; C064658:RAG-1 protein; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases