Bidirectional blockade of CD4 and major histocompatibility complex class II molecules: an effective immunosuppressive treatment in the mouse heart transplantation model.
BACKGROUND
Anti-CD4 monoclonal antibodies (mabs) are powerful immunosuppressive agents. However, in experimental models anti-CD4 treatment alone is not always completely effective. Anti-major histocompatibility complex (MHC) class II mabs may have a synergistic effect with anti-CD4 mab therapy by blocking the function of both antigen-presenting cells and T cells.


METHODS
C3H/He mice (H-2k: I-Ak, I-Ek) received a vascularized cardiac graft from C57BL/10 (H-2b: I-Ab) or BALB/c (H-2d: I-Ad, I-Ed) mice and were treated with a depleting anti-CD4 or a depleting anti-MHC class II antibody either alone or in combination.


RESULTS
Anti-CD4 treatment alone prolonged graft survival in both strain combinations but was only minimally effective when BALB/c donors were used. However, when anti-CD4 and anti-MHC class II mabs were administered together, graft survival was significantly prolonged in both strain combinations. The ratio of interleukin-4 (IL-4)/interferon-gamma (IFN-gamma) expressed in both C57BL/10- and BALB/c-transplanted hearts 7 days after transplantation was significantly higher after combined treatment with anti-CD4 plus anti-MHC class II mabs compared with that found after either treatment alone. Twenty-one days after transplantation, the ratio of IL-4/IFN-gamma in BALB/c hearts after combined mab therapy was significantly lower than at 7 days after transplantation, but in contrast, the cytokine ratio in C57BL/10 hearts remained at an elevated level during the first 21 days after transplantation.


CONCLUSIONS
These data demonstrate that bidirectional blockade of the antigen-presenting cell and T-cell interaction by use of anti-CD4 and anti-MHC class II mabs in combination is more effective than either treatment alone. Graft survival in this model seems to correlate with a prolonged elevation of the IL-4/IFN-gamma ratio in the transplanted heart, suggesting that in this model the induction of unresponsiveness may be associated with a shift toward a Th2-type T-cell response.
Ito
H
H
First Department of Surgery, Yamaguchi University School of Medicine, Ube, Japan.
Hamano
K
K
Fukumoto
T
T
Wood
K J
KJ
Esato
K
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015704:CD4 Antigens / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D015847:Interleukin-4; D007371:Interferon-gamma