Induction of tolerance with nondepleting anti-CD4 monoclonal antibodies is associated with down-regulation of TH2 cytokines.
BACKGROUND
Induction of tolerance with anti-CD4 has mainly focused on monoclonal antibodies (mAbs) that deplete CD4+ T cells. In this study, the mechanisms by which nondepleting anti-CD4 mAbs induce tolerance in the Dark Agouti to PVG rat heart graft model were examined.


METHODS
Five anti-CD4 mAbs were tested. Immunohistology and cytokine mRNA profiles were analyzed within grafts. Effects of combining anti-CD4 therapy with alloantibody (alloAb), interleukin (IL)-4, and anti-IL-4 mAb were also examined.


RESULTS
All mAbs tested induced indefinite graft survival (>150 days), with blocking of alloAb production. Exogenous alloAb did not restore rejection. Similar T cell receptor alphabeta+, CD8+, IL-2 receptor+ T cell, macrophage, and natural killer cell infiltration and comparable MHC II and intercellular adhesion molecule-1 levels were seen in rejecting and tolerant grafts. mRNA for IL-2, interferon-gamma, lymphotoxin, tumor necrosis factor-alpha, transforming growth factor-beta, cytolysin, and granzyme-A/B was comparable, although inducible nitric oxide synthase was slightly reduced in tolerant grafts. IL-4 and IL-5 were significantly reduced in tolerant grafts, although IL-6, IL-10, and IL-13 levels were similar; this was consistent with partial T helper (Th)2 response inhibition, which was also manifested by inhibited alloAb. The combination of alloAb, IL-4, or anti-IL-4 mAb with anti-CD4 did not prevent tolerance induction.


CONCLUSIONS
This study demonstrated that anti-CD4 mAb therapy did not inhibit activation and infiltration of Th1 and CD8+ effector T cells. Preferential induction of Th2 responses, especially IL-4, was not essential for the induction of tolerance. Our studies also found no evidence to support induction of anergy or transforming growth factor-beta as mechanisms of tolerance induction. These results question whether IL-4 is required for induction of transplantation tolerance.
Plain
K M
KM
University of New South Wales, Department of Medicine, Liverpool Hospital, Australia.
Fava
L
L
Spinelli
A
A
He
X Y
XY
Chen
J
J
Boyd
R
R
Davidson
C L
CL
Hall
B M
BM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015704:CD4 Antigens / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006085:Graft Survival / Q000187:drug effects; D007165:Immunosuppression Therapy; D015847:Interleukin-4 / Q000494:pharmacology; D007518:Isoantibodies / Q000276:immunology; D051379:Mice; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018418:Th2 Cells / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016207:Cytokines; D007518:Isoantibodies; D012333:RNA, Messenger; D015847:Interleukin-4