CD28 blockade alters cytokine mRNA profiles in cardiac transplantation.
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-gamma (IFN-gamma), 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-gamma 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-gamma, with a resultant predominant IL-10 driven, Th2 tolerogenic response.
Lin
H
H
Section of Thoracic Surgery, University of Michigan Medical Center, Ann Arbor, USA.
Wei
R Q
RQ
Goodman
R E
RE
Bolling
S F
SF
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology*; D000961:Antilymphocyte Serum / Q000494:pharmacology; D018106:CD28 Antigens / Q000502:physiology*; D060908:CTLA-4 Antigen; D003520:Cyclophosphamide / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007519:Isoantigens / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects; D014184:Transplantation, Homologous
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000961:Antilymphocyte Serum; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556708:Ctla4 protein, rat; D016207:Cytokines; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007519:Isoantigens; D012333:RNA, Messenger; D016753:Interleukin-10; D015847:Interleukin-4; D000069594:Abatacept; D007371:Interferon-gamma; D016572:Cyclosporine; D003520:Cyclophosphamide