The Role of the IL-2 Pathway in Costimulation Blockade-Resistant Rejection of Allografts

• Published in: The Journal of immunology (1950) Vol. 168; no. 3; pp. 1123 - 1130
• Main Authors: Jones, Thomas R, Ha, Jongwon, Williams, Matthew A, Adams, Andrew B, Durham, Megan M, Rees, Phyllis A, Cowan, Shannon R, Pearson, Thomas C, Larsen, Christian P
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.02.2002
• Subjects: Abatacept; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; Antigens, CD; Antigens, Differentiation - administration & dosage; CD25 antigen; CD28 antigen; CD4-Positive T-Lymphocytes - immunology; CD40 antigen; CD40 Ligand - immunology; CD8-Positive T-Lymphocytes - immunology; CTLA-4 Antigen; Cytotoxicity Tests, Immunologic; Down-Regulation - immunology; Drug Synergism; Graft Rejection - immunology; Graft Rejection - prevention & control; Graft Survival - immunology; Graft vs Host Disease - immunology; Immune Sera - administration & dosage; Immunoconjugates; Immunosuppressive Agents - pharmacology; Injections, Intraperitoneal; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - biosynthesis; interleukin 2 receptors; Interleukin-2 - antagonists & inhibitors; Interleukin-2 - immunology; Interleukin-2 - physiology; Lymphocyte Activation - immunology; Lymphocyte Culture Test, Mixed; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Receptors, Interleukin-2 - immunology; Signal Transduction - immunology; Skin Transplantation - immunology; Transplantation, Homologous - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.168.3.1123

Blockade of the CD40 and CD28 costimulatory pathways significantly prolongs allograft survival; however, certain strains of mice (i.e., C57BL/6) are relatively resistant to the effects of combined CD40/CD28 blockade. We have previously shown that the costimulation blockade-resistant phenotype can be attributed to a subset of CD8+ T cells and is independent of CD4+ T cell-mediated help. Here we explore the role of the IL-2 pathway in this process using mAbs against the high affinity IL-2R, CD25, and IL-2 in prolonging skin allograft survival in mice receiving combined CD40/CD28 blockade. We have also investigated the effects of treatment on effector function by assessment of cytotoxicity and the generation of IFN-gamma-producing cells in response to allogeneic stimulators as well as proliferation in an in vivo graft-vs-host disease model. We find that additional blockade of either CD25 or IL-2 significantly extends allograft survival beyond that in mice receiving costimulation blockade alone. This correlates with diminished frequencies of IFN-gamma-producing allospecific T cells and reduced CTL activity. Anti-CD25 therapy also synergizes with CD40/CD28 blockade in suppressing proliferative responses. Interestingly, depletion of CD4+ T cells, but not CD8+ cells, prevents prolongation in allograft survival, suggesting an IL-2-independent role for regulation in extended survival.