The Journal of Experimental Medicine
IN Cell Analyzer 2000
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 118K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Koblish, H. K.
Right arrow Articles by Lee, W. M.F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Koblish, H. K.
Right arrow Articles by Lee, W. M.F.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?
© The Rockefeller University Press, 0022-1007/1998/11/1603/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 9, November 2, 1998 1603-1610

Articles

Immune Suppression by Recombinant Interleukin (rIL)-12 Involves Interferon {gamma} Induction of Nitric Oxide Synthase 2 (iNOS) Activity: Inhibitors of NO Generation Reveal the Extent of rIL-12 Vaccine Adjuvant Effect

Holly Kurzawa Koblish*, Christopher A. Hunter§, Maria Wysocka||, Giorgio Trinchieri||, and William M.F. Lee{ddagger},||

From the * Cell and Molecular Biology Graduate Group and the {ddagger} Department of Medicine, Cancer Center, and Institute for Human Gene Therapy, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; the § School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; and || The Wistar Institute, Philadelphia, Pennsylvania 19104

Recombinant interleukin 12 (IL-12) can profoundly suppress cellular immune responses in mice. To define the underlying mechanism, recombinant murine (rm)IL-12 was given to C57BL/6 mice undergoing alloimmunization and found to transiently but profoundly suppress in vivo and in vitro allogeneic responses and in vitro splenocyte mitogenic responses. Use of neutralizing antibodies and genetically deficient mice showed that IFN-{gamma} (but not TNF-{alpha}) mediated rmIL-12–induced immune suppression. Splenocyte fractionation studies revealed that adherent cells from rmIL-12–treated mice suppressed the mitogenic response of normal nonadherent cells to concanavalin A and IL-2. Addition of an inhibitor of nitric oxide synthase (NOS) restored mitogenic responses, and inducible (i)NOS–/– mice were not immunosuppressed by rmIL-12. These results support the view that suppression of T cell responses is due to NO produced by macrophages responding to the high levels of IFN-{gamma} induced by rmIL-12. When a NOS inhibitor was given with rmIL-12 during vaccination of A/J mice with irradiated SCK tumor cells, immunosuppression was averted and the extent of rmIL-12's ability to enhance induction of protective antitumor immunity was revealed. This demonstrates that rmIL-12 is an effective vaccine adjuvant whose efficacy may be masked by its transient immunosuppressive effect.

Key Words: interleukin 12 • immunosuppression • interferon {gamma} • nitric oxide • nitric oxide synthase 2

Address correspondence to William M.F. Lee, 663 Clinical Research Building, 415 Curie Blvd., University of Pennsylvania, Philadelphia, PA 19104-6140. Phone: 215-898-0258; Fax: 215-573-7912; E-mail: leemingf @mail.med.upenn.edu

Abbreviations used: D-NAME, N-nitro-D-arginine methyl ester; D-NMMA, N-methyl-D-arginine; DTH, delayed-type hypersensitivity; iNOS, inducible nitric oxide synthase; LCMV, lymphocytic choriomeningitis virus; L-NAME, N-nitro-L-arginine methyl ester; L-NMMA, N-methyl-L-arginine; NO, nitric oxide; SCK.GM cells, SCK tumor cells engineered to secrete GM-CSF.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS