CD28 blockade alters cytokine mRNA profiles in cardiac transplantation

• Published in: Surgery 1997-08, Vol.122 (2), p.129-137
• Main Authors: Lin, Hua, Wei, Ru-Qi, Goodman, Richard E, Bolling, Steven F
• Format: Article
• Language: English
• Subjects: Abatacept; Animals; Antigens, CD; Antigens, Differentiation - pharmacology; Antilymphocyte Serum - pharmacology; CD28 Antigens - physiology; CTLA-4 Antigen; Cyclophosphamide - pharmacology; Cyclosporine - pharmacology; Cytokines - biosynthesis; Graft Survival - immunology; Heart Transplantation - immunology; Immunoconjugates; Immunosuppressive Agents - pharmacology; Interferon-gamma - biosynthesis; Interleukin-10 - biosynthesis; Interleukin-2 - biosynthesis; Interleukin-4 - biosynthesis; Isoantigens - pharmacology; Lymphocyte Activation; Male; Polymerase Chain Reaction - methods; Rats; Rats, Inbred BN; Rats, Inbred Lew; RNA, Messenger - biosynthesis; T-Lymphocytes - immunology; Th1 Cells - immunology; Th2 Cells - immunology; Transcription, Genetic - drug effects; Transplantation, Homologous
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1016/S0039-6060(97)90001-5

Background. T-cell response to alloantigen is dependent on T-cell receptor activation and costimulation through the CD28 receptor, because T-cell receptor activation alone is insufficient for optimal immune response. The CD28 receptor on helper T cells interacts with its ligand B7 on activated B cells-macrophages as costimulus to support T-cell activity. CTLA4Ig is a recombinant inhibitor of CD28 receptor activation. In vivo studies with a rat major histocompatibility complex mismatch heterotopic cardiac transplant model demonstrate that CTLA4Ig prolongs cardiac allograft survival. This CTLA4Ig survival benefit is enhanced with prior donor-specific antigen exposure. Methods. To investigate CTLA4Ig mechanisms, we examined the differential expression of B7 and cytokine mRNAs for interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4, and IL-10 (Th1 or Th2 activation) in cardiac allografts after treatment with CTLA4Ig and donor-specific antigen exposure versus conventional immunotherapy (cyclosporine, cyclophosphamide, or antilymphocyte serum). In the above major histocompatibility complex mismatch model, hearts (on day 5 after transplantation at peak rejection) had cytokine mRNA expression determined by semiquantitative reverse transcriptase-polymerase chain reaction. Results. Inhibition of B7 expression was observed in CTLA4Ig animals. Expression of IL-2 and IFN-γ was near undetectable in CTLA4Ig and cyclophosphamide rats but was only moderately reduced by cyclosporine and antilymphocyte serum. IL-4 mRNA expression was reduced equally in all animals. Finally, IL-10 levels were unchanged by CTLA4Ig but were decreased by other therapies. Conclusions. The beneficial effect of CTLA4Ig, inhibiting expression of B7, alters Th1 cytokines IL-2 and IFN-γ, with a resultant predominant IL-10 driven, Th2 tolerogenic response.