Peritransplant tolerance induction with anti-CD3-immunotoxin: a matter of proinflammatory cytokine control.

Academic Article

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.
  • Published In

  • Transplantation  Journal
  • Keywords

  • Animals, Antibodies, Monoclonal, CD3 Complex, Cytokines, Graft Survival, Guanidines, Immune Tolerance, Immunosuppressive Agents, Immunotoxins, Inflammation Mediators, Interferon-gamma, Interleukin-12, Kidney Transplantation, Macaca mulatta, Male, NF-kappa B, Phytohemagglutinins
  • Authorlist

  • Contreras JL; Wang PX; Eckhoff DE; Lobashevsky AL; Asiedu C; Frenette L; Robbin ML; Hubbard WJ; Cartner S; Nadler S
  • Start Page

  • 1159
  • End Page

  • 1169
  • Volume

  • 65
  • Issue

  • 9