title: Peritransplant tolerance induction with anti-CD3-immunotoxin: a matter of proinflammatory cytokine control.
abstract: BACKGROUND
  Tolerance is gaining momentum as an approach to reduce lifelong immunosuppressive therapy while improving transplant longevity. Anti-CD3 immunotoxin (IT), FN18-CRM9, has potential to induce tolerance owing to its exceptional ability to deplete sessile lymph node T cells. However, if initiated at the time of transplantation, alpha-CD3-IT alone elicits a proinflammatory cytokine response, precluding establishment of tolerance.
  
  
  METHODS
  Four groups of rhesus monkeys received kidney allografts and immunosuppression. Three groups received alpha-CD3-IT alone or alpha-CD3-IT supplemented with 15-deoxyspergualin (DSG) and/or methylprednisolone (MP). One group received alpha-CD3-monoclonal antibody with DSG and MP. Cytokines were measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Supplementing peritransplant alpha-CD3-IT treatment with a brief course of DSG and MP promoted rejection-free kidney allograft acceptance in 75% of macaques followed for up to 550 days. Among those given alpha-CD3-IT alone or with MP, none were long-term survivors. Tolerance developed after alpha-CD3-IT, DSG, and MP treatment, but not when the unconjugated a-CD3 monoclonal antibody was substituted for IT. Systemic production of proinflammatory cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha induced after peritransplant alpha-CD3-IT was prevented only in animals given DSG. Despite high levels of interleukin (IL)-12 in the first month after transplant, tolerant recipients exhibited IL-12 resistance, as evidenced by baseline plasma levels of IFN-gamma but elevated IL-4. DSG was shown to inhibit IL-12-driven IFN-gamma production by a mechanism associated with inhibition of nuclear factor kappa-B.
  
  
  CONCLUSIONS
  In this model, peritransplant induction of tolerance is promoted by efficient elimination of sessile lymph node T cells and control of the proinflammatory IFN-gamma response by a mechanism that appears to involve resistance to IL-12.
authors.affiliation: Department of Surgery and Transplant Center, University of Alabama at Birmingham, 35294, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Contreras
authors.forename: P X
authors.initials: PX
authors.lastname: Wang
authors.forename: D E
authors.initials: DE
authors.lastname: Eckhoff
authors.forename: A L
authors.initials: AL
authors.lastname: Lobashevsky
authors.forename: C
authors.initials: C
authors.lastname: Asiedu
authors.forename: L
authors.initials: L
authors.lastname: Frenette
authors.forename: M L
authors.initials: ML
authors.lastname: Robbin
authors.forename: W J
authors.initials: WJ
authors.lastname: Hubbard
authors.forename: S
authors.initials: S
authors.lastname: Cartner
authors.forename: S
authors.initials: S
authors.lastname: Nadler
authors.forename: W J
authors.initials: WJ
authors.lastname: Cook
authors.forename: J
authors.initials: J
authors.lastname: Sharff
authors.forename: J
authors.initials: J
authors.lastname: Shiloach
authors.forename: F T
authors.initials: FT
authors.lastname: Thomas
authors.forename: D M
authors.initials: DM
authors.lastname: Neville
authors.forename: J M
authors.initials: JM
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D006085:Graft Survival / Q000502:physiology; D006146:Guanidines / Q000494:pharmacology; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000494:pharmacology; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology; D016030:Kidney Transplantation; D008253:Macaca mulatta; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010835:Phytohemagglutinins / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016207:Cytokines; D006146:Guanidines; D007166:Immunosuppressive Agents; D000922:Immunotoxins; D018836:Inflammation Mediators; D016328:NF-kappa B; D010835:Phytohemagglutinins; D018664:Interleukin-12; D007371:Interferon-gamma; C037258:gusperimus