B7-1 (CD80), B7-2 (CD86), InterLeukin-12 & Transforming Growth Factor-ß mRNA Expression In CSF & Peripheral Blood MonoNuclear Cells In Multiple Sclerosis
Monteyne P, Guillaume B, Sindic CJ
J NeuroImmunol 1998 Nov 2;91(1-2):198-203
Catholic Univ of Louvain, Laboratory of NeuroChemistry, Brussels, Belgium
PMID# 9846836; UI# 99061293
CoStimulatory molecules B7-1 (CD80) and B7-2 (CD86) are differently involved in T-Cell stimulation. In Chronic Experimental AutoImmune EncephaloMyelitis (EAE) model of Multiple Sclerosis (MS), B7-1 was preferentially involved in PathoPhysiology of relapses.
We used Reverse Transcription Polymerase Chain Reaction (RT-PCR) to amplify the mRNA coding for these molecules in CerebroSpinal Fluid (CSF) Cells and Peripheral Blood MonoNuclear Cells (PBMC) from 18 MS patients and 21 Other Neurological patients.
In CSF cells of MS cases, B7-1 mRNA was only detected in some patients who showed clinical signs of acute relapse at the time of the Spinal Tap, while B7-2 mRNA was widely detectable without difference between active or stable MS and controls.
mRNA coding for Transforming Growth Factor-ß (TGF-ß) was detectable in the majority of cases.
With higher expression in CSF cells of MS and Other Inflammatory Neurological Diseases (OIND) than in NonInflammatory controls, and higher expression in PBMC of MS patients than in all other cases.
Finally, mRNA coding for InterLeukin (IL)-12p40 was only detected in a very few number of MS and Inflammatory cases.
These findings were related to previous detection of other Cytokines in the same cases, showing relationships in CSF cells between high expression of B7-1, IL-12p40 and TNF-.
Anti-IL-12 AntiBody Prevents The Development And Progression Of Multiple Sclerosis - Like Relapsing/Remitting DeMyelinating Disease In NOD Mice Induced With Myelin Oligodendrocyte Glycoprotein Peptide
Ichikawa M, Koh CS, Inoue A, Tsuyusaki J, Yamazaki M, Inaba Y, Sekiguchi Y, Itoh M, Yagita H, Komiyama A
J NeuroImmunol 2000 Jan 3;102(1):56-66
Shinshu Univ, School of Medicine, Dept of Pediatrics, Asahi, Matsumoto, Japan
PMID# 10626667; UI# 20090093
Treatment with MonoClonal Anti-IL-12 AntiBody injected on day 0, 7 and 10 after immunization with Myelin Oligodendrocyte Glycoprotein (MOG) peptide 35-55 in NOD mice.
Resulted in significant suppression of the development and the severity of the chronic Relapsing/Remitting Experimental AutoImmune EncephaloMyelitis (EAE) both clinically and histologically.
The Spleen Cells from Anti-IL-12 AntiBody treated mice displayed markedly inhibited MOG35-55 specific proliferation and IFN-γ production.
MOG35-55 specific AntiBody production was enhanced by anti-IL-12 AntiBody treatment.
These results suggest that IL-12 is critically involved in the PathoGenesis of MOG-induced EAE and that AntiBody to IL-12 could be an effective therapeutic agent in the clinical treatment of AutoImmune DeMyelinating Diseases such as Multiple Sclerosis (MS).
Cytokine Secretion Of Myelin Basic Protein Reactive T-Cells In Multiple Sclerosis
Windhagen A, Anderson DE, Carrizosa A, Balashov K, Weiner HL, Hafler DA
J NeuroImmunol 1998 Nov 2;91(1-2):1-9
Brigham and Women's Hospital, and Harvard Medical School, Center for Neurologic Diseases, Dept of Neurology, Boston, MA 02115-5817, USA
PMID# 9846813; UI# 99061270
The objective of this study was to determine whether AutoReactive T-Cells in patients with Multiple Sclerosis (MS) are polarized and committed in their differentiation to a stable Cytokine phenotype or whether the Cytokine secretion can be altered.
We examined the Cytokines secreted by Myelin Basic Protein (MBP) as compared to Tetanus Toxoid-reactive (TT) T-Cells in 12 patients with Relapsing/Remitting MS (RR-MS), 9 patients with Chronic/Progressive MS (CP-MS), and 14 normal individuals.
A total of 5094 short term T-Cell lines to MBP and TT were generated in the presence of growth conditions promoting Th1 (IL-12/alpha-IL-4 mAb) or Th2 (IL-4/alpha-IL-12 mAb) Cytokine secretion.
Antigen-specific Cytokine secretion from normals and MS patients could be shifted to a Th1 or Th2 type phenotype depending upon culture conditions, indicating that the phenotype of MBP reactive T-Cells can be altered even in longstanding Chronic/Progressive MS.
There were no significant differences in the Cytokine patterns secreted by MBP reactive T-Cells in patients with MS as compared to normal individuals.
However, CP-MS patients tended to have fewer MBP reactive T-Cells secreting IL-4 when cultured with IL-12/anti-IL-4 mAb and more IFN-γ (IFN-γ) secreting MBP reactive T-Cells when cultured with IL-4/anti-IL-12 mAb as compared to both normal controls and RR-MS.
Suggesting thaT-Cells from these patients might be more polarized or that fewer undifferentiated MBP-reactive cells are present in these individuals.
The most striking observation was that in contrast to the RR-MS patients and normal controls, almost none of the MBP reactive T-Cells secreting Cytokines in CP-MS incorporated 3[H]Thymidine.
This may be due to chronic in vivo stimulation in the presence of IL-12, or because these T-Cells may have entered a terminally differentiated state.
Nonetheless, the ability to alter the Cytokine secretion of AutoReactive T-Cell lines even in longstanding AutoImmune Disease indicates that Cytokine therapy might have therapeutic benefits by switching the function of Myelin reactive T-Cells such that they are Non-Pathogenic.
Impaired InterLeukin-12 Production In MS
Rohowsky-Kochan C, Molinaro D, Choudhry A, Kahn M, Cook SD
Mult Scler 1999 Oct;5(5):327-34
New Jersey Medical School, Dept of NeuroSciences,
Univ of Medicine & Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA
PMID# 10516776; UI# 99448053
Multiple Sclerosis (MS), a disease of the human Central Nervous System, is believed to be a T-Cell mediated AutoImmune Disorder with Genetic and Environmental influences.
InterLeukin-12 (IL-12), a ProInflammatory Cytokine produced primarily by Antigen Presenting Cells, a potent inducer of Interferon-gamma (IFN-γ), and other Th1 Cytokines that may play an important role in MS PathoGenesis.
We have investigated IL-12 production induced by the T-Cell independent pathway in untreated and IFN-ß treated MS patients, healthy individuals, and Other Neurological Disease (OND) patients in response to the human Pathogen Staphylococcus Aureus.
We report that Peripheral Blood MonoNuclear Cells (PBMC), from untreated MS patients, produce normal amounts of the biologically active IL-12 p70 heterodimer.
But significantly less free IL-12 p40 heavy chain than PBMC from both healthy and disease controls, when challenged in vitro with Staphylococcus Aureus.
Both mRNA expression of the inducible IL-12 p40 chain and protein levels were found to be reduced in untreated MS patients.
No decrease in the production of the IL-12 p40 was seen in MS patients on IFN-ß therapy.
The decreased production of IL-12 p40 heavy chain is not attributed to increased IL-10 secretion, a defect in the production of Cytokines by Macrophages or the number of Cytokine producing cells.
The factor(s) responsible for the decrease in p40 remain to be determined.
Since IL-12 p40 antagonizes the biological activity of IL-12 in vitro and in vivo, identification of a defect in the 'natural' antagonist of IL-12, may provide the basis for Immune therapy.