Interleukin-12 (IL-12)-driven alloimmune responses in vitro and in vivo: requirement for beta1 subunit of the IL-12 receptor

• Published in: Transplantation Vol. 67; no. 11; pp. 1453 - 1460
• Main Authors: Piccotti, J R, Li, K, Chan, S Y, Eichwald, E J, Bishop, D K
• Format: Journal Article
• Language: English
• Published: United States 15-06-1999
• Subjects: AIDS/HIV; Animals; Antibody Formation - drug effects; Dose-Response Relationship, Drug; Epitopes - immunology; Female; Graft Rejection - drug therapy; Heart Transplantation - immunology; Interleukin-12 - metabolism; Interleukin-12 - pharmacology; Isoantigens - genetics; Isoantigens - immunology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Phenotype; Receptors, Interleukin - metabolism; Recombinant Proteins - pharmacology; Th1 Cells - physiology; Transplantation, Homologous - physiology
• ISSN: 0041-1337

Interleukin-12 (IL-12) mediates its biologic activities via binding high-affinity receptors on T and natural killer cells. Although emphasis has been placed on the requirement for IL-12Rbeta2 in IL-12 bioactivity, the role of IL-12Rbeta1 is less well defined. The current study evaluated the effects of exogenous IL-12 on alloantigen-specific immune responses and determined the requirement for IL-12Rbeta1 in IL-12-mediated alloimmunity.
The mouse heterotopic cardiac transplant model was employed to evaluate the effects of IL-12 on alloantigen-specific immune responses in vivo. In addition, IFN-gamma production in mixed lymphocyte cultures (MLC) supplemented with IL-12 was measured to assess the effects of IL-12 on Th1 function in vitro. Mice deficient in IL-12Rbeta1 (IL-12Rbeta1-/-) were used to determine the requirement for this receptor component in IL-12-driven alloimmune responses.
Addition of IL-12 to MLC consisting of wild-type splenocytes enhanced alloantigen-specific proliferative responses and Th1 development. In contrast, IL-12 did not alter these in vitro immune parameters in IL-12Rbeta1-/- MLC. Treatment of wild-type cardiac allograft recipients with IL-12 resulted in high concentrations of serum interferon-gamma (IFN-gamma) and a 10-fold increase in IFN-gamma production by recipient splenocytes after restimulation in vitro. However, this fulminate Th1 response did not accelerate allograft rejection. Importantly, IL-12 had no effect on serum IFN-gamma or in vivo priming of Thl in IL-12Rbeta1-/- recipients. Finally, administration of IL-12 to WT allograft recipients resulted in a bimodal alloantibody response: antibody production was suppressed at high doses of IL-12, and enhanced at lower doses.
IL-12 markedly enhances alloantigen-specific immune function; however, these exaggerated Th1-driven responses do not culminate in accelerated allograft rejection. Further, these data indicate that IL-12Rbeta1 is essential for the enhancement of both in vitro and in vivo alloimmune responses by exogenous IL-12.