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1.
Cytokine ; 148: 155599, 2021 12.
Article in English | MEDLINE | ID: mdl-34103211

ABSTRACT

Interleukin-15 (IL-15) is a pleiotropic cytokine that plays pivotal roles in innate and adaptive immunity. It is also a promising cytokine for treating cancer. Despite growing interest in its use as an immunotherapeutic, its safety and immunological effects in dogs have not been reported. In this study, healthy dogs were given recombinant canine IL-15 (rcIL-15) intravenously at a daily dose of 20 µg/kg for 8 days and monitored for 32 days to determine the safety and immunological effects of rcIL-15. The repeated administration of rcIL-15 was well tolerated, did not cause any serious side effects, and promoted the selective proliferation and activation of canine anti-cancer effector cells, including CD3+CD8+ cytotoxic T lymphocytes, CD3+CD5dimCD21-, and non-B/non-T NK cell populations, without stimulating Treg lymphocytes. The rcIL-15 injections also stimulated the expression of molecules and transcription factors associated with the activation and effector functions of NK cells, including CD16, NKG2D, NKp30, NKp44, NKp46, perforin, granzyme B, Ly49, T-bet, and Eomes. These results suggest that rcIL-15 might be a valuable therapeutic adjuvant to improve immunity against cancer in dogs.


Subject(s)
Interleukin-15/adverse effects , Interleukin-15/immunology , Recombinant Proteins/adverse effects , Recombinant Proteins/immunology , Animals , Antigens, CD/metabolism , Cell Proliferation/drug effects , Cytotoxicity, Immunologic/drug effects , Dogs/blood , Forkhead Transcription Factors/metabolism , Gene Expression Regulation/drug effects , Granzymes/metabolism , Humans , Interleukin-15/administration & dosage , Interleukin-15/toxicity , K562 Cells , Killer Cells, Natural/metabolism , Leukocyte Count , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lymphocyte Subsets/drug effects , Lymphocyte Subsets/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Recombinant Proteins/administration & dosage , Recombinant Proteins/toxicity , T-Box Domain Proteins/metabolism
2.
J Immunother Cancer ; 9(4)2021 04.
Article in English | MEDLINE | ID: mdl-33883258

ABSTRACT

BACKGROUND: Full application of cytokines as oncoimmunotherapeutics requires identification of optimal regimens. Our initial effort with intravenous bolus recombinant human interleukin-15 (rhIL-15) was limited by postinfusional reactions. Subcutaneous injection and continuous intravenous infusion for 10 days (CIV-10) provided rhIL-15 with less toxicity with CIV-10 giving the best increases in CD8+ lymphocytes and natural killer (NK) cells. To ease rhIL-15 administration, we shortened time of infusion. Treatment with rhIL-15 at a dose of 3-5 µg/kg as a 5-day continuous intravenous infusion (CIV-5) had no dose-limiting toxicities while effector cell stimulation was comparable to the CIV-10 regimen. METHODS: Eleven patients with metastatic cancers were treated with rhIL-15 CIV-5, 3 µg (n=4), 4 µg (n=3), and 5 µg/kg/day (n=4) in a phase I dose-escalation study (April 6, 2012). RESULTS: Impressive expansions of NK cells were seen at all dose levels (mean 34-fold), including CD56bright NK cells (mean 144-fold for 4 µg/kg), as well as an increase in CD8+ T cells (mean 3.38-fold). At 5 µg/kg/day, there were no dose-limiting toxicities but pulmonary capillary leak and slower patient recovery. This led to our choice of the 4 µg/kg as CIV-5 dose for further testing. Cytolytic capacity of CD56bright and CD56dim NK cells was increased by interleukin-15 assayed by antibody-dependent cellular cytotoxicity (ADCC), natural cytotoxicity and natural killer group 2D-mediated cytotoxicity. The best response was stable disease. CONCLUSIONS: IL-15 administered as CIV-5 substantially expanded NK cells with increased cytotoxic functions. Tumor-targeting monoclonal antibodies dependent on ADCC as their mechanism of action including alemtuzumab, obinutuzumab, avelumab, and mogamulizumab could benefit from those NK cell expansions and provide a promising therapeutic strategy. TRIAL REGISTRATION NUMBERS: NCT01572493, NCT03759184, NCT03905135, NCT04185220 and NCT02689453.


Subject(s)
Antineoplastic Agents/administration & dosage , Cell Proliferation/drug effects , Interleukin-15/administration & dosage , Killer Cells, Natural/drug effects , Lymphocyte Activation/drug effects , Neoplasms/drug therapy , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Coculture Techniques , Cytokines/metabolism , Cytotoxicity, Immunologic/drug effects , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Interleukin-15/adverse effects , K562 Cells , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lymphocyte Count , Male , Maryland , Middle Aged , Neoplasm Metastasis , Neoplasms/immunology , Neoplasms/metabolism , Time Factors , Treatment Outcome
3.
Int Immunopharmacol ; 91: 107318, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33383444

ABSTRACT

Interleukin-15 (IL-15) has recently emerged as a novel immunomodulatory cytokine in cancer immunotherapy. IL-15 has the potential to reject and destroy cancer cells in the tumor microenvironment by expanding and activating natural killer (NK), natural killer T (NKT), and memory (m) CD8+T cells. Due to the feasible outcomes obtained from preclinical studies and phase 1/2 clinical trials, IL-15-based therapy, including chimeric antigen receptor (CAR) T cell or CAR NK cell infusion following in vitro expansion in the presence of IL-15, used in combination with checkpoint inhibitors and other therapy may extend to clinical practice in the future. It is also important to understand the biological characteristics of IL-15 to ensure the maximal benefit of therapeutic strategies. Here, we summarize the current development of IL-15 in the following areas: anti-tumor mechanisms in the tumor microenvironment, advances in IL-15-based therapy itself or in combination with other methods, including biological agents, monoclonal antibodies, and adoptive immunotherapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Immune System/drug effects , Immunotherapy , Interleukin-15/therapeutic use , Lymphocytes, Tumor-Infiltrating/drug effects , Neoplasms/drug therapy , Tumor Microenvironment/drug effects , Adaptive Immunity/drug effects , Animals , Antineoplastic Agents/adverse effects , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cytotoxicity, Immunologic/drug effects , Humans , Immune System/immunology , Immune System/metabolism , Immunity, Innate/drug effects , Immunotherapy/adverse effects , Interleukin-15/adverse effects , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Neoplasms/immunology , Neoplasms/metabolism , Neoplasms/pathology , Treatment Outcome
4.
J Infect Dis ; 221(4): 523-533, 2020 02 03.
Article in English | MEDLINE | ID: mdl-31562760

ABSTRACT

BACKGROUND: The PD1/PD-L1 pathway contributes to the pathogenesis of human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, and blockade of this pathway may have potential to restore immune function and promote viral control or elimination. In this study, we combined a checkpoint inhibitor anti-PD-L1 (Avelumab) and recombinant human interleukin-15 (rhIL-15) in SIV-infected rhesus macaques (RM). METHODS: The rhIL-15 was administered as continuous infusion in 2 cycles of 10 days in the context of weekly administration of anti-PD-L1 (Avelumab) in SIV-infected RM receiving combination antiretroviral therapy (cART). Safety, immunological parameters, and viral loads were monitored during the study. RESULTS: Administration of rhIL-15/anti-PD-L1 was safe and well tolerated. Treatment resulted in transient increases in proliferating (Ki67+) natural killer and CD8 T cells. In addition, treatment expanded a CXCR3+PD1-/low CD8 T-cell subset with the ability to secrete cytokines. Despite these effects, no changes in plasma viremia were observed after cART interruption. CONCLUSIONS: Expansion of the CXCR3+PD1-/low CD8 T-cell subset with functional capacity and potential to traffic to sites of viral reservoirs in SIV-infected rhesus macaques had no demonstrable effect on plasma viremia after cART interruption.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , CD8-Positive T-Lymphocytes/immunology , Interleukin-15/therapeutic use , Programmed Cell Death 1 Receptor/metabolism , Receptors, CXCR3/metabolism , Simian Acquired Immunodeficiency Syndrome/drug therapy , Simian Immunodeficiency Virus , Animals , Antibodies, Monoclonal, Humanized/adverse effects , Drug Therapy, Combination , Female , Humans , Interleukin-15/adverse effects , Interleukin-15/genetics , Macaca mulatta , Male , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/virology , Treatment Outcome , Viral Load/drug effects
5.
Blood Adv ; 3(13): 1970-1980, 2019 07 09.
Article in English | MEDLINE | ID: mdl-31266741

ABSTRACT

In vivo expansion of haploidentical natural killer (NK) cell infusions with interleukin-2 (IL-2) can induce remission of refractory acute myeloid leukemia, but efficacy may be hampered by concurrent stimulation of host regulatory T cells. To overcome this limitation, we substituted the NK homeostatic factor IL-15 in 2 phase 1/2 trials. Forty-two patients received either intravenous (IV) (NCT01385423) or subcutaneous (SC) (NCT02395822) recombinant human IL-15 (rhIL-15) after lymphodepleting chemotherapy and haploidentical NK cells. Escalating doses of rhIL-15 (0.3-1.0 µg/kg) were given on 12 consecutive days in a phase 1 trial. Of 26 patients, 36% had robust in vivo NK-cell expansion at day 14, and 32% achieved complete remission. Hypothesizing that SC dosing of rhIL-15 would be safer and better tolerated, 16 patients received 10 once per day doses of SC rhIL-15 at 2.0 µg/kg on a phase 2 trial. NK-cell expansion at day 14 was seen in 27% of the patients, and 40% achieved remission. rhIL-15 induced better rates of in vivo NK-cell expansion and remission compared with previous trials with IL-2, but it was associated with previously unreported cytokine release syndrome (CRS) after SC but not IV dosing. CRS was observed in 56% of patients given SC rhIL-15 (with concurrent neurologic toxicity in 5 of 9 patients) and was responsive to steroids and tocilizumab. SC administration was associated with slower pharmacokinetic clearance and higher levels of IL-6 than IV dosing. These novel trials testing the use of IL-15 to potentiate cell therapy suggest that dosing schedules based on pharmacokinetics and pharmacodynamics will preserve the therapeutic benefits of IL-15 and minimize CRS. These trials were registered at www.clinicaltrials.gov as #NCT01385423 and #NCT02395822.


Subject(s)
Immunotherapy, Adoptive , Interleukin-15/therapeutic use , Killer Cells, Natural/transplantation , Leukemia, Myeloid, Acute/therapy , Adult , Aged , Combined Modality Therapy , Drug Resistance, Neoplasm , Female , Humans , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Interleukin-15/administration & dosage , Interleukin-15/adverse effects , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Recurrence , Transplantation, Haploidentical , Young Adult
6.
Clin Cancer Res ; 25(16): 4945-4954, 2019 08 15.
Article in English | MEDLINE | ID: mdl-31142503

ABSTRACT

PURPOSE: The first-in-human clinical trial with human bolus intravenous infusion IL15 (rhIL15) was limited by treatment-associated toxicity. Here, we report toxicity, immunomodulation, and clinical activity of rhIL15 administered as a 10-day continuous intravenous infusion (CIV) to patients with cancers in a phase I trial. PATIENTS AND METHODS: Patients received treatment for 10 days with CIV rhIL15 in doses of 0.125, 0.25, 0.5, 1, 2, or 4 µg/kg/day. Correlative laboratory tests included IL15 pharmacokinetic (PK) analyses, and assessment of changes in lymphocyte subset numbers. RESULTS: Twenty-seven patients were treated with rhIL15; 2 µg/kg/day was identified as the MTD. There were eight serious adverse events including two bleeding events, papilledema, uveitis, pneumonitis, duodenal erosions, and two deaths (one due to likely drug-related gastrointestinal ischemia). Evidence of antitumor effects was observed in several patients, but stable disease was the best response noted. Patients in the 2 µg/kg/day group had a 5.8-fold increase in number of circulating CD8+ T cells, 38-fold increase in total NK cells, and 358-fold increase in CD56bright NK cells. Serum IL15 concentrations were markedly lower during the last 3 days of infusion. CONCLUSIONS: This phase I trial identified the MTD for CIV rhIL15 and defined a treatment regimen that produced significant expansions of CD8+ T and NK effector cells in circulation and tumor deposits. This regimen has identified several biological features, including dramatic increases in numbers of NK cells, supporting trials of IL15 with anticancer mAbs to increase antibody-dependent cell-mediated cytotoxicity and anticancer efficacy.


Subject(s)
Interleukin-15/administration & dosage , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Lymphocyte Subsets/drug effects , Lymphocyte Subsets/immunology , Neoplasms/drug therapy , Neoplasms/immunology , Cytokines/metabolism , Female , Humans , Immunohistochemistry , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Immunologic Factors/pharmacokinetics , Immunomodulation/drug effects , Inflammation Mediators/metabolism , Infusions, Intravenous , Interleukin-15/adverse effects , Interleukin-15/pharmacokinetics , Killer Cells, Natural/metabolism , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Lymphocyte Count , Lymphocyte Subsets/metabolism , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Neoplasms/diagnosis , Neoplasms/metabolism , Treatment Outcome
7.
J Immunol ; 201(5): 1570-1585, 2018 09 01.
Article in English | MEDLINE | ID: mdl-30068596

ABSTRACT

Malignant cell growth within patients with B cell chronic lymphocytic leukemia (B-CLL) is largely restricted to lymphoid tissues, particularly lymph nodes. The recent in vitro finding that TLR-9 ligand (oligodeoxynucleotide [ODN]) and IL-15 exhibit strong synergy in promoting B-CLL growth may be particularly relevant to growth in these sites. This study shows IL-15-producing cells are prevalent within B-CLL-infiltrated lymph nodes and, using purified B-CLL cells from blood, investigates the mechanism for ODN and IL-15 synergy in driving B-CLL growth. ODN boosts baseline levels of phospho-RelA(S529) in B-CLL and promotes NF-κB-driven increases in IL15RA and IL2RB mRNA, followed by elevated IL-15Rα and IL-2/IL-15Rß (CD122) protein. IL-15→CD122 signaling during a critical interval, 20 to 36-48 h following initial ODN exposure, is required for optimal induction of the cycling process. Furthermore, experiments with neutralizing anti-IL-15 and anti-CD122 mAbs indicate that clonal expansion requires continued IL-15/CD122 signaling during cycling. The latter is consistent with evidence of heightened IL2RB mRNA in the fraction of recently proliferated B-CLL cells within patient peripheral blood. Compromised ODN+IL-15 growth with limited cell density is consistent with a role for upregulated IL-15Rα in facilitating homotypic trans IL-15 signaling, although there may be other explanations. Together, the findings show that ODN and IL-15 elicit temporally distinct signals that function in a coordinated manner to drive B-CLL clonal expansion.


Subject(s)
Cell Proliferation/drug effects , Interleukin-15/adverse effects , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Oligodeoxyribonucleotides/adverse effects , Signal Transduction/drug effects , Drug Synergism , Female , Humans , Interleukin-15/agonists , Interleukin-15/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Oligodeoxyribonucleotides/pharmacology , Signal Transduction/immunology
8.
J Clin Oncol ; 33(1): 74-82, 2015 Jan 01.
Article in English | MEDLINE | ID: mdl-25403209

ABSTRACT

PURPOSE: Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy. PATIENTS AND METHODS: We performed a first in-human trial of Escherichia coli-produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 µg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer. RESULTS: Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 µg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 µg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients. CONCLUSION: IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration.


Subject(s)
CD4-Positive T-Lymphocytes/drug effects , Cell Proliferation/drug effects , Interleukin-15/therapeutic use , Killer Cells, Natural/drug effects , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Area Under Curve , CD4-Positive T-Lymphocytes/metabolism , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Fever/chemically induced , Humans , Infusions, Intravenous , Interleukin-15/adverse effects , Interleukin-15/genetics , Killer Cells, Natural/metabolism , Lymphocyte Activation/drug effects , Male , Metabolic Clearance Rate , Middle Aged , Nausea/chemically induced , Neoplasm Metastasis , Neoplasms/immunology , Neoplasms/metabolism , Neutropenia/chemically induced , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacokinetics , Recombinant Proteins/therapeutic use , Treatment Outcome , Young Adult
9.
Blood ; 118(9): 2520-9, 2011 Sep 01.
Article in English | MEDLINE | ID: mdl-21757617

ABSTRACT

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 Load
10.
Cytokine Growth Factor Rev ; 22(2): 99-108, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21531164

ABSTRACT

Interleukin 15 participates in the development of important immune antitumor mechanisms. It activates CD8(+) T cells, natural killer (NK) cells, NK T cells, and can promote the formation of antitumor antibodies. IL-15 can also protect T effector cells from the action of T regulatory cells and reverse tolerance to tumor-associated antigens. In pre-clinical studies IL-15 has been found to demonstrate potentiated antitumor effects following pre-association with IL-15Rα, or when used in combination with chemotherapy, adoptive therapy, monoclonal antibodies, and tumor vaccines. Although a clinical trial based on application of IL-15 in tumor patients has already begun, it is important to be aware of its potential side effects, including induction of autoimmunity and promotion of proliferation, survival, and dissemination of some tumor cells.


Subject(s)
Immunotherapy , Interleukin-15/therapeutic use , Neoplasms/therapy , Antineoplastic Agents/therapeutic use , Cancer Vaccines/immunology , Humans , Interleukin-15/adverse effects , Interleukin-15/physiology , Killer Cells, Natural/immunology , Neoplasms/immunology , Signal Transduction , T-Lymphocytes/immunology
11.
Blood Cells Mol Dis ; 27(1): 223-30, 2001.
Article in English | MEDLINE | ID: mdl-11358383

ABSTRACT

The role of inflammation in the early genesis of certain malignancies has recently been appreciated. Interleukin (IL)-15, a proinflammatory cytokine and growth factor, is required for lymphocyte homeostasis. Intriguingly, the expression of IL-15 protein is tightly controlled by multiple posttranscriptional mechanisms, suggesting that inappropriate expression of IL-15 may be detrimental to the host. We recently engineered a transgenic mouse in which the normal posttranscriptional control of IL-15 is eliminated, thereby overexpressing the murine IL-15 protein. IL-15 transgenic mice have early expansions in NK and CD8+ T lymphocytes and later develop fatal lymphocytic leukemia with a T-NK phenotype. This article recapitulates the phenotype of these IL-15 transgenic mice and discusses the utility of this model as a tool to further our understanding of leukemogenesis.


Subject(s)
Disease Models, Animal , Interleukin-15/adverse effects , Leukemia, T-Cell/etiology , Animals , Cell Transformation, Neoplastic/drug effects , Humans , Interleukin-15/genetics , Killer Cells, Natural , Leukemia, T-Cell/mortality , Mice , Mice, Transgenic
12.
J Immunol ; 162(8): 4943-51, 1999 Apr 15.
Article in English | MEDLINE | ID: mdl-10202041

ABSTRACT

The mechanism of cytokine-induced shock remains poorly understood. The combination of IL-2 and IL-12 has synergistic antitumor activity in vivo, yet has been associated with significant toxicity. We examined the effects of IL-2 plus IL-12 in a murine model and found that the daily, simultaneous administration of IL-2 and IL-12 resulted in shock and 100% mortality within 4 to 12 days depending on the strain employed. Mice treated with IL-2 plus IL-12 exhibited NK cell apoptosis, pulmonary edema, degenerative lesions of the gastrointestinal tract, and elevated serum levels of proinflammatory cytokines and acute phase reactants. The actions of TNF-alpha, IFN-gamma, macrophage-inflammatory protein-1alpha, IL-1, IL-1-converting enzyme, Fas, perforin, inducible nitric oxide synthase, and STAT1 did not contribute to the observed toxicity, nor did B or T cells. However, toxicity and death from treatment with IL-2 plus IL-12 could be completely abrogated by elimination of NK cells. These results suggest that the fatal systemic inflammatory response induced by this cytokine treatment is critically dependent upon NK cells, but does not appear to be mediated by the known effector molecules of this cellular compartment. These data may provide insight into the pathogenesis of cytokine-induced shock in humans.


Subject(s)
Interleukins/adverse effects , Killer Cells, Natural/immunology , Shock, Septic/etiology , Shock, Septic/mortality , Animals , Cell Separation , Cytokines/biosynthesis , Cytokines/blood , Drug Therapy, Combination , Female , Interferon-gamma/physiology , Interleukin-1/physiology , Interleukin-12/administration & dosage , Interleukin-12/adverse effects , Interleukin-15/administration & dosage , Interleukin-15/adverse effects , Interleukin-2/administration & dosage , Interleukin-2/adverse effects , Interleukins/administration & dosage , Liver/pathology , Lung/pathology , Macrophage Activation , Macrophages/immunology , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, SCID , Mice, Transgenic , Monocytes/immunology , Shock, Septic/immunology , Shock, Septic/pathology , Spleen/pathology , Tumor Necrosis Factor-alpha/physiology
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