Intragraft overexpression of interleukin-4 is neither sufficient nor essential for tolerance induction to cardiac allografts in a high-responder strain combination.
BACKGROUND
Recently we have demonstrated that the nondepleting anti-CD4 monoclonal antibody (mAb) RIB5/2 induces long-term acceptance of kidney and heart allografts in all rat strain combinations tested. Cytokine gene expression studies by reverse transcriptase-polymerase chain reaction revealed a reversed intragraft interleukin (IL)-4/interferon-gamma ratio. Whether IL-4 mediated immune deviation contributes to transplantation tolerance is not clear so far.


METHODS
To learn more about the functional relevance of the relative IL-4 up-regulation, IL-4 was overexpressed in rat heart allografts by using ex vivo adenoviral gene transfer. The efficiency of gene transfer was analyzed by reporter gene assays as well by reverse transcriptase-polymerase chain reaction analysis of IL-4 mRNA expression.


RESULTS
The intragraft overexpression of IL-4 did not prolong the allograft survival compared with controls. Moreover, neutralization of IL-4 by OX81 mAb did not prevent tolerance induction by RIB5/2 treatment.


CONCLUSIONS
Anti-CD4 mAb-induced tolerance is associated with an intragraft type1/type2 shift, however, the up-regulation of IL-4 alone is neither sufficient nor essential to induce tolerance to cardiac allografts in a high-responder strain combination.
Ritter
T
T
Institute of Medical Immunology and Clinic of Nephrology & Internal Intensive Care, Charité, Humboldt-University Berlin, Germany. thomas.ritter@charite.de
Risch
K
K
Schroder
G
G
Kolls
J
J
Siegling
A
A
Graser
E
E
Reinke
P
P
Brock
J
J
Lehmann
M
M
Volk
H D
HD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D018014:Gene Transfer Techniques; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015847:Interleukin-4