Antibodies to interleukin 12 abrogate established experimental colitis in mice.

In this study, we describe a novel murine model of chronic intestinal inflammation induced by the hapten reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). Rectal application of low doses of TNBS in BALB/c and SJL/J mice resulted in a chronic transmural colitis with severe diarrhea, weight loss, and rectal prolapse, an illness that mimics some characteristics of Crohn's disease in humans. The colon of TNBS-treated mice on day 7 was marked by infiltration of CD4+ T cells; furthermore, in situ polymerase chain reaction studies revealed high levels of interferon (IFN)-gamma mRNA in diseased colons. Isolated lamina propria (LP) CD4+ T cells from TNBS-treated mice stimulated with anti-CD3 and anti-CD28 antibodies exhibited a Th1 pattern of cytokine secretion: a 20-50-fold increase in IL-2 and IFN-gamma levels and a 5-fold decrease in IL-4 levels as compared with those of stimulated LP CD4+ T cells from control BALB/c mice. Administration of monoclonal anti-IL-12 antibodies to the TNBS-treated mice both early (at 5 d) and late (at 20 d) after induction of colitis led to a striking improvement in both the clinical and histopathological aspects of the disease and frequently abrogated the established colitis completely. Furthermore, LP CD4+ T cells isolated from anti-IL-12-treated mice failed to secrete IFN-gamma upon in vitro stimulation. In summary, the data demonstrate the pivotal role of IL-12 and IFN-gamma in a TNBS-induced murine model of chronic intestinal inflammation. Furthermore, they suggest the potential utility of anti-IL-12 antibodies in patients with Crohn's disease.

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Increased expression of tumor necrosis factor in peripheral blood memory CD4+ T cells of patients with Crohn's disease

Gastroenterology ◽

10.1016/s0016-5085(01)81574-2 ◽

2001 ◽

Vol 120 (5) ◽

pp. A317-A317

Author(s):

J DETENA ◽

L MANZANO ◽

J LEAL ◽

A PRIETO ◽

E ANTONIO ◽

...

Keyword(s):

T Cells ◽

Crohn’S Disease ◽

Tumor Necrosis Factor ◽

Crohn's Disease ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Tumor Necrosis ◽

Memory Cd4 T Cells ◽

Necrosis Factor

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Distinctive Pattern of Cytokine Production and Adhesion Molecule Expression in Peripheral Blood Memory CD4+ T Cells from Patients with Active Crohn’s Disease

Journal of Clinical Immunology ◽

10.1007/s10875-006-9016-4 ◽

2006 ◽

Vol 26 (3) ◽

pp. 233-242 ◽

Cited By ~ 9

Author(s):

Jaime García De Tena ◽

Luis Manzano ◽

Juan Carlos Leal ◽

Esther San Antonio ◽

Verónica Sualdea ◽

...

Keyword(s):

T Cells ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Adhesion Molecule ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Cytokine Production ◽

Adhesion Molecule Expression ◽

Distinctive Pattern ◽

Memory Cd4 T Cells

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Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice

International Immunology ◽

10.1093/intimm/5.11.1461 ◽

1993 ◽

Vol 5 (11) ◽

pp. 1461-1471 ◽

Cited By ~ 767

Author(s):

Flona Powrie ◽

Michael W. Leach ◽

Smita Mauze ◽

Linda Barcomb Caddie ◽

Robert L. Coffman

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Intestinal Inflammation ◽

Scid Mice ◽

Chronic Intestinal Inflammation

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Tu1801 - Pro-Inflammatory Gene Network Regulated by Novel Long Non-Coding Rnas in Crohn's Disease-Associated Cd4 + T Cells

Gastroenterology ◽

10.1016/s0016-5085(18)33427-9 ◽

2018 ◽

Vol 154 (6) ◽

pp. S-1023

Author(s):

Manuel Bonfim Braga Neto ◽

Olga F. Sarmento ◽

Phyllis Svingen ◽

Michelle Gonzalez ◽

Joseph M. Gaballa ◽

...

Keyword(s):

T Cells ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Cd4 T Cells ◽

Gene Network ◽

Inflammatory Gene ◽

Non Coding Rnas

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Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection.

Journal of Experimental Medicine ◽

10.1084/jem.179.2.447 ◽

1994 ◽

Vol 179 (2) ◽

pp. 447-456 ◽

Cited By ~ 231

Author(s):

S L Reiner ◽

S Zheng ◽

Z E Wang ◽

L Stowring ◽

R M Locksley

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Leishmania Major ◽

Interleukin 12 ◽

Insect Vector ◽

T Helper 1 ◽

Ifn Gamma ◽

Effector Cells

Leishmania major are intramacrophage parasites whose eradication requires the induction of T helper 1 (Th1) effector cells capable of activating macrophages to a microbicidal state. Interleukin 12 (IL-12) has been recently identified as a macrophage-derived cytokine capable of mediating Th1 effector cell development, and of markedly enhancing interferon gamma (IFN-gamma) production by T cells and natural killer cells. Infection of macrophages in vitro by promastigotes of L. major caused no induction of IL-12 p40 transcripts, whereas stimulation using heat-killed Listeria or bacterial lipopolysaccharide induced readily detectable IL-12 mRNA. Using a competitor construct to quantitate a number of transcripts, a kinetic analysis of cytokine induction during the first few days of infection by L. major was performed. All strains of mice examined, including susceptible BALB/c and resistant C57BL/6, B10.D2, and C3H/HeN, had the appearance of a CD4+ population in the draining lymph nodes that contained transcripts for IL-2, IL-4, and IFN-gamma (and in some cases, IL-10) that peaked 4 d after infection. In resistant mice, the transcripts for IL-2, IL-4, and IL-10 were subsequently downregulated, whereas in susceptible BALB/c mice, these transcripts were only slightly decreased, and IL-4 continued to be reexpressed at high levels. IL-12 transcripts were first detected in vivo by 7 d after infection, consistent with induction by intracellular amastigotes. Challenge of macrophages in vitro confirmed that amastigotes, in contrast to promastigotes, induced IL-12 p40 mRNA. Reexamination of the cytokine mRNA at 4 d revealed expression of IL-13 in all strains analyzed, suggesting that IL-2 and IL-13 may mediate the IL-12-independent production of IFN-gamma during the first days after infection. Leishmania have evolved to avoid inducing IL-12 from host macrophages during transmission from the insect vector, and cause a striking induction of mRNAs for IL-2, IL-4, IL-10, and IL-13 in CD4+ T cells. Each of these activities may favor survival of the organism.

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