Treatment with interleukin-4 prolongs allogeneic neonatal heart graft survival by inducing T helper 2 responses.
BACKGROUND
The T helper (Th) 2 cytokine interleukin (IL)-4 has been implicated as a major regulatory cytokine for the induction of transplant tolerance, but few studies have examined the capacity of IL-4 to induce tolerance. The effect of IL-4 therapy alone or with low doses of anti-CD4 monoclonal antibody (mAb) therapy on survival of fully allogeneic PVG neonatal heart graft in adult DA rats was examined.


METHODS
Rat recombinant (r) IL-4 was given at 30 microg (10(4) U)/kg daily intraperitoneally for 10 days and MRC OX35 (anti-CD4, nondepleting) or MRC OX81 (anti-IL-4) was given intraperitoneally on days 0, 3, 7, and 10. Semiquantitative reverse transcriptase-polymerase chain reaction was used to assay mRNA for cytokine in the graft, regional node and spleen and fluorescence-activated cell sorting was used to assay alloantibody Ig isotypes.


RESULTS
Grafts in rIL-4-treated rats survived a median period of 39 days (range, 28-52 days), significantly longer than in both untreated and nontransfected Chinese hamster ovary-K1 supernatant-treated controls (median, 14 days; range, 10-16 days, P=0.009). rIL-4 treatment with a suboptimal dose of anti-CD4 mAb prolonged median survival to 70 days (range, 63-80 days), which was longer than rIL-4 treatment alone or anti-CD4 mAb alone (median, 36 days; range, 30-55 days; P<0.0045). Combining MRC OX81 with MRC OX35 therapy led to earlier rejection at a median period of 26 days (range, 20-28 days); MRC OX81 alone had no effect on graft survival. Alloantibody titers, especially IgG1, were higher in rIL-4-treated animals and lower in anti-CD4 mAb-treated animals than in animals with normal rejection (P<0.05). IL-4 mRNA was increased in regional lymph nodes and spleen of the rIL-4-treated groups compared with all other groups, but there were no differences for IL-2, interferon-gamma, or IL-10.


CONCLUSIONS
rIL-4 therapy markedly prolonged neonatal cardiac allograft survival, and, with anti-CD4 therapy, it further prolonged survival. It induced IL-4 mRNA in lymphoid tissues and enhanced alloantibody production, especially IgG1, which demonstrated enhanced Th2 responses, but did not affect Th1 cytokines.
He
X Y
XY
Department of Medicine, University of New South Wales, Liverpool Hospital, Australia.
Chen
J
J
Verma
N
N
Plain
K
K
Tran
G
G
Hall
B M
BM
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015704:CD4 Antigens / Q000276:immunology; D016466:CHO Cells; D006224:Cricetinae; D016207:Cytokines / Q000235:genetics; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D015847:Interleukin-4 / Q000276:immunology / Q000627:therapeutic use*; D007518:Isoantibodies / Q000096:biosynthesis; D008221:Lymphoid Tissue / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000502:physiology*; D013997:Time Factors; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016207:Cytokines; D007518:Isoantibodies; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015847:Interleukin-4