ABSTRACT
Chronic kidney disease (CKD), secondary to renal fibrogenesis, is a public health burden. The activation of interstitial myofibroblasts and excessive production of extracellular matrix (ECM) proteins are major events leading to end-stage kidney disease. Recently, interleukin-15 (IL-15) has been implicated in fibrosis protection in several organs, with little evidence in the kidney. Since endogenous IL-15 expression decreased in nephrectomized human allografts evolving toward fibrosis and kidneys in the unilateral ureteral obstruction (UUO) model, we explored IL-15's renoprotective role by pharmologically delivering IL-15 coupled or not with its soluble receptor IL-15Rα. Despite the lack of effects on myofibroblast accumulation, both IL-15 treatments prevented tubulointerstitial fibrosis (TIF) in UUO as characterized by reduced collagen and fibronectin deposition. Moreover, IL-15 treatments inhibited collagen and fibronectin secretion by transforming growth factor-ß (TGF-ß)-treated primary myofibroblast cultures, demonstrating that the antifibrotic effect of IL-15 in UUO acts, in part, through a direct inhibition of ECM synthesis by myofibroblasts. In addition, IL-15 treatments resulted in decreased expression of monocyte chemoattractant protein 1 (MCP-1) and subsequent macrophage infiltration in UUO. Taken together, our study highlights a major role of IL-15 on myofibroblasts and macrophages, two main effector cells in renal fibrosis, demonstrating that IL-15 may represent a new therapeutic option for CKD.
Subject(s)
Interleukin-15 Receptor alpha Subunit/therapeutic use , Interleukin-15/therapeutic use , Kidney/metabolism , Nephrosclerosis/prevention & control , Renal Insufficiency, Chronic/drug therapy , Animals , Chemokine CCL2/metabolism , Collagen/biosynthesis , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Interleukin-15/metabolism , Interleukin-15/pharmacology , Interleukin-15 Receptor alpha Subunit/metabolism , Kidney/pathology , Mice, Inbred C57BL , Myofibroblasts/drug effects , Myofibroblasts/metabolism , Renal Insufficiency, Chronic/metabolism , Ureteral ObstructionABSTRACT
Rheumatoid arthritis (RA) is a chronic, destructive inflammatory autoimmune disease. Cytokine-mediated immunity has been found to play an important role in the pathogenesis of autoimmune diseases including RA. Recently, much attention has been paid on the role of IL-15, which is a member of the 4 α-helix bundle cytokine family. IL-15 was detected in serum and synovial fluid from RA patients and arthritis mice models. Moreover, administration of IL-15 leads to the development of severe inflammatory arthritis, suggesting that IL-15 may be therapeutically relevant in RA. Therefore, targeting IL-15 may be significantly important and valuable. In this article, we discuss the biological features and effects of IL-15 and summarize recent advances on the pathological roles of IL-15 in RA and treatment for RA.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/etiology , Immunologic Factors/therapeutic use , Interleukin-15/therapeutic use , Animals , Disease Models, Animal , Drug Evaluation, Preclinical , Gene Expression Regulation/drug effects , Humans , Immunologic Factors/pharmacology , Interleukin-15/chemistry , Interleukin-15/pharmacology , Interleukin-15/physiology , Signal Transduction/drug effectsABSTRACT
Inflammatory bowel diseases are commonly complicated by weight and bone loss. We hypothesized that IL-15, a pro-inflammatory cytokine expressed in colitis and an osteoclastogenic factor, could play a central role in systemic and skeletal complications of inflammatory bowel diseases. We evaluated the effects of an IL-15 antagonist, CRB-15, in mice with chronic colitis induced by oral 2% dextran sulfate sodium for 1 week, followed by another 1% for 2 weeks. During the last 2 weeks, mice were treated daily with CRB-15 or an IgG2a control antibody. Intestinal inflammation, disease severity, and bone parameters were evaluated at days 14 and 21. CRB-15 improved survival, early weight loss, and colitis clinical score, although colon damage and inflammation were prevented in only half the survivors. CRB-15 also delayed loss of femur bone mineral density and trabecular microarchitecture. Bone loss was characterized by decreased bone formation, but increased bone marrow osteoclast progenitors and osteoclast numbers on bone surfaces. CRB-15 prevented the suppression of osteoblastic markers of bone formation, and reduced osteoclast progenitors at day 14, but not later. However, by day 21, CRB-15 decreased tumor necrosis factor α and increased IL-10 expression in bone, paralleling a reduction of osteoclasts. These results delineate the role of IL-15 on the systemic and skeletal manifestations of chronic colitis and provide a proof-of-concept for future therapeutic developments.
Subject(s)
Colitis/prevention & control , Interleukin-15/antagonists & inhibitors , Osteoporosis/prevention & control , Recombinant Fusion Proteins/therapeutic use , Animals , Body Weight/drug effects , Bone Density/drug effects , Bone Marrow/metabolism , Chronic Disease , Colitis/chemically induced , Colitis/complications , Colitis/physiopathology , Cytokines/metabolism , Dextran Sulfate , Drug Evaluation, Preclinical/methods , Female , Femur/pathology , Femur/physiopathology , Inflammation Mediators/metabolism , Interleukin-15/pharmacology , Interleukin-15/therapeutic use , Mice , Mice, Inbred C57BL , Osteoblasts/drug effects , Osteoblasts/pathology , Osteoclasts/drug effects , Osteoclasts/pathology , Osteoporosis/etiology , Osteoporosis/pathology , Osteoporosis/physiopathology , Recombinant Fusion Proteins/pharmacology , Severity of Illness Index , Survival AnalysisABSTRACT
No disponible
Subject(s)
Child , Humans , Celiac Disease/diagnosis , Clinical Diagnosis , Celiac Disease/diet therapy , Celiac Disease/drug therapy , HLA Antigens/therapeutic use , Interleukin-15/therapeutic use , Diet, Gluten-FreeABSTRACT
Human immunodeficiency virus (HIV) infection is characterized by a progressive loss of memory CD4(+) T cells in multiple tissues, especially at mucosal surfaces where most of these cells reside. Although antiretroviral therapy (ART) suppresses viral replication and promotes the recovery of peripheral CD4(+) T cells, HIV-infected patients fail to fully reconstitute the CD4(+) T-cell pool at mucosal sites. IL-15 has been shown to preferentially expand memory-phenotype T cells and promote their migration to nonlymphoid tissues. Here we examined IL-15 treatment in combination with highly active ART in chronically SIV-infected rhesus macaques and found that IL-15 delayed viral suppression and failed to enhance ART-induced total and antigen-specific CD4(+) T-cell reconstitution at mucosal and lymphoid sites. IL-15 was able to induce the transient proliferation of SIV-specific, CMV-specific, and total memory CD8(+) T cells, but not of SIV-specific or total CD4(+) T cells. Moreover, upon treatment interruption, macaques receiving combined IL-15+ART lost CD4(+) T cells faster than those receiving ART alone. These results suggest that the combination of IL-15 with highly active ART is not more efficient than ART alone in promoting CD4(+) T-cell recovery in HIV-infected individuals and may accelerate CD4+ T-cell loss after treatment interruption.
Subject(s)
Adenine/analogs & derivatives , Anti-Retroviral Agents/therapeutic use , CD4-Positive T-Lymphocytes/drug effects , Deoxycytidine/analogs & derivatives , Immunologic Factors/therapeutic use , Interleukin-15/therapeutic use , Organophosphonates/therapeutic use , Pyrrolidinones/therapeutic use , Simian Acquired Immunodeficiency Syndrome/immunology , Adaptive Immunity/drug effects , Adenine/administration & dosage , Adenine/pharmacology , Adenine/therapeutic use , Animals , Anti-Retroviral Agents/administration & dosage , Anti-Retroviral Agents/pharmacology , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , Deoxycytidine/administration & dosage , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Drug Evaluation, Preclinical , Drug Therapy, Combination , Emtricitabine , Immunity, Mucosal/drug effects , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Immunologic Factors/pharmacology , Immunotherapy , Interleukin-15/administration & dosage , Interleukin-15/adverse effects , Interleukin-15/pharmacology , Lymphocyte Activation , Lymphoid Tissue/immunology , Lymphoid Tissue/pathology , Macaca mulatta , Mucous Membrane/immunology , Mucous Membrane/pathology , Organophosphonates/administration & dosage , Organophosphonates/pharmacology , Pyrrolidinones/administration & dosage , Pyrrolidinones/pharmacology , Raltegravir Potassium , Random Allocation , Tenofovir , Treatment Failure , Viral LoadABSTRACT
Blockade of the CTLA-4 and PD-1 inhibitory pathways in T cells via the administration of neutralizing antibodies at the time of interleukin (IL)-15 therapy markedly enhanced the survival of tumor-bearing mice as compared with those receiving IL-15 alone or IL-15 in combination with just one of the antibodies.
Subject(s)
Antibodies, Neutralizing/pharmacology , Immune Tolerance/drug effects , Interleukin-15/therapeutic use , Neoplasms/drug therapy , Animals , Antibodies, Neutralizing/administration & dosage , Antigens, CD/immunology , Antigens, CD/metabolism , Antigens, CD/physiology , Antigens, Differentiation/immunology , Antigens, Differentiation/metabolism , Antigens, Differentiation/physiology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , CTLA-4 Antigen , Cell Line, Tumor , Disease Models, Animal , Drug Evaluation, Preclinical , Drug Synergism , Immune Tolerance/immunology , Immunotherapy/methods , Mice , Models, Biological , Neoplasm Metastasis , Neoplasms/immunology , Neoplasms/mortality , Neoplasms/pathology , Programmed Cell Death 1 Receptor , Signal Transduction/drug effects , Signal Transduction/immunology , Treatment OutcomeABSTRACT
PURPOSE: Interleukin 15 (IL-15) is a promising cytokine for immunotherapy of cancer due to its ability to stimulate the immunity of natural killer, B, and T cells. Its effectiveness, however, may be limited by inhibitory checkpoints and pathways that can attenuate immune responses. Finding strategies to abrogate these negative regulators and enhance the efficacy of IL-15 is a critical challenge. EXPERIMENTAL DESIGN: In a preclinical study, we evaluated IL-15 combined with antibodies to block the negative immune regulators cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) in a metastatic murine CT26 colon carcinoma model. RESULTS: IL-15 treatment resulted in a significant prolongation of survival in mice with metastatic tumor. Administration of IL-15, however, also increased expression of PD-1 on the surface of CD8(+) T cells including CD8(+)CD44(high) memory phenotype T cells. Moreover, IL-15 also increased the secretion of the immunosuppressive cytokine, IL-10. Combining IL-15 with anti-PD-L1 and anti-CTLA-4 (multiple immune checkpoint blockade) exhibited greater CTL killing and IFNγ secretion. Moreover, this combination resulted in a significant reduction in surface expression of PD-1 on CD8(+) T cells, a decrease in IL-10 secretion, and led to significantly longer survival of tumor-bearing animals compared with mice treated with IL-15 alone or combined singularly with anti-PD-L1 or anti-CTLA-4. CONCLUSIONS: Combining the immune stimulatory properties of IL-15 with the simultaneous removal of 2 critical immune system inhibitory checkpoints, we showed enhancement of immune responses leading to increased antitumor activity.
Subject(s)
Antibodies, Neutralizing/pharmacology , Carcinoma/drug therapy , Colonic Neoplasms/drug therapy , Immune Tolerance/drug effects , Interleukin-15/therapeutic use , Animals , Antibodies, Neutralizing/administration & dosage , Antigens, CD/immunology , Antigens, CD/metabolism , Antigens, CD/physiology , Antigens, Differentiation/immunology , Antigens, Differentiation/metabolism , Antigens, Differentiation/physiology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , CTLA-4 Antigen , Carcinoma/immunology , Carcinoma/mortality , Carcinoma/pathology , Cell Line, Tumor , Colonic Neoplasms/immunology , Colonic Neoplasms/mortality , Colonic Neoplasms/pathology , Disease Models, Animal , Drug Evaluation, Preclinical , Drug Synergism , Female , Immune Tolerance/immunology , Immunotherapy/methods , Mice , Mice, Inbred BALB C , Models, Biological , Neoplasm Metastasis , Programmed Cell Death 1 Receptor , Signal Transduction/drug effects , Signal Transduction/immunology , Treatment OutcomeSubject(s)
HIV Infections/therapy , Immunotherapy , Interleukin-15/therapeutic use , T-Lymphocyte Subsets/drug effects , Adjuvants, Immunologic , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Cytokines/physiology , Drug Evaluation, Preclinical , HIV/drug effects , HIV/physiology , HIV Infections/immunology , Humans , Immunologic Memory/drug effects , Interleukin-15/biosynthesis , Interleukin-15/deficiency , Interleukin-15/pharmacology , Killer Cells, Natural/immunology , Lymphocytes/metabolism , T-Lymphocyte Subsets/immunology , Virus Replication/drug effectsABSTRACT
IL-15 is a powerful T cell growth factor (TCGF) with particular importance for the maintenance of CD8(+) T cells. Because costimulation blockade does not result in universal tolerance, we hypothesized that "escape" from costimulation blockade might represent a CD8(+) and IL-15/IL-15R(+)-dependent process. For this analysis, we have used an IL-15 mutant/Fcgamma2a protein, a potentially cytolytic protein that is also a high-affinity receptor site specific antagonist for the IL-15Ralpha receptor protein, as a therapeutic agent. The IL-15-related fusion protein was used as monotherapy or in combination with CTLA4/Fc in murine islet allograft models. As monotherapies, CTLA4/Fc and an IL-15 mutant/Fcgamma2a were comparably effective in a semiallogeneic model system, and combined treatment with IL-15 mutant/Fcgamma2a plus CTLA4/Fc produced universal permanent engraftment. In a fully MHC-mismatched strain combination known to be refractory to costimulation blockade treatment, combined treatment with both fusion proteins proved to be highly effective; >70% of recipients were tolerized. The analysis revealed that the IL-15 mutant/Fc treatment confers partial protection from both CD4(+) and CD8(+) T cell graft infiltration. In rejections occurring despite CTLA4/Fc treatment, concomitant treatment with the IL-15 mutant/Fcgamma2a protein blocked a CD8(+) T cell-dominated rejection processes. This protection was linked to a blunted proliferative response of alloreactive T cells as well silencing of CTL-related gene expression events. Hence, we have demonstrated that targeting the IL-15/IL-15R pathway represents a new and potent strategy to prevent costimulation blockade-resistant CD8(+) T cell-driven rejection.