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Dambuza 1, Chang He 1,2, Cheng-Rong Yu 1, 1, Mary J.
We show here that the IL-12p35, the alpha subunit of IL-12 or IL-35 cytokine, might be an effective biologic for suppressing neuroinflammatory responses and ameliorating the pathology of experimental autoimmune encephalomyelitis EAEthe mouse model of human MS.
We further show that IL-12p35 conferred protection from neuropathy by inhibiting the expansion of pathogenic Th17 and Th1 cells and inhibiting trafficking of inflammatory cells into the brain and spinal cord.
In addition, in vitro exposure of encephalitogenic cells to IL-12p35 suppressed their capacity to induce EAE by adoptive transfer.
Moreover, IL-12p35 inhibited lymphocyte proliferation by suppressing the expressions of cell-cycle regulatory proteins.
Taken together, these results suggest that IL-12p35 can be exploited as a novel biologic for treating central nervous system autoimmune diseases and offers the promise of ex vivo production of large amounts of Tregs and Bregs for immunotherapy.
Introduction Multiple sclerosis MS is a complex inflammatory 4 and degenerative disease thought to be triggered by blood-borne leukocytes that invade the central nervous system CNS.
These cells produce inflammatory cytokines such as IL-17 and IFN-γ that act on CNS-resident cells microglia and astrocytes to elicit production of additional cytokines IL-1, IL-6, IL-12, IL-23, and TNF-α and chemokines that promote further recruitment of leukocytes, which fuel the inflammatory cascade .
Besides the major histocompatibility complex loci, cytokines are among the most associated risk factor genes for MS and therefore a major target of disease-modifying therapies immune suppressants, steroids, immune modulators, and biologics for the treatment of MS.
Experimental autoimmune encephalomyelitis EAE is the prototypical animal model of MS.
Much of what we have learned about the pathophysiology of MS has come from EAE, which has also provided valuable insights into therapeutic approaches that might be effective in MS.
Autoreactive Th1 and Th17 cells activated at peripheral sites traffic from the draining lymph nodes, cross the blood—brain or blood—cerebrospinal fluid barrier and mediate CNS pathology .
The requirement of pathogen-associated molecular patterns PAMPs contained in CFA for induction of EAE has led to interest in pathways that regulate cytokines elicited in response to PAMPs.
There are currently four known members of this family, IL-12, IL-23, IL-27, and IL-35 —.
Each member is composed of two subunits; an alpha subunit structurally similar to the IL-6 superfamily cytokines p19, p28, and p35 and a beta subunit homologous to type 1 cytokine receptors p40 and Ebi3.
Published reports suggest that the predominant IL-12 family member produced within the environment of differentiating naïve lymphocytes significantly influences their developmental decisions and might therefore determine the lymphocyte subsets that would dominate the ensuing immune response.
There is now consensus that IL-12 and IL-23 are pro-inflammatory while IL-35 4 immune suppressive and a prime candidate 4 a biologic that can be used to suppress autoimmune diseases.
That IL-35 is of critical importance in ameliorating CNS autoimmune diseases was demonstrated by several studies indicating that IL-35 can induce the expansion of Treg cells and a unique IL-35-producing regulatory B cell i35-Breg population—.
However, isolating or producing sufficient quantities of the functional IL-35 heterodimeric cytokine has been challenging and very labor intensive .
Thus far, this has been a major impediment for ex vivo production of large scale IL-35-producing Bregs for adoptive Breg therapy.
An important question concerning the immunobiology of IL-35 relates to the relative contributions of IL-12p35 or Ebi3 subunit to the biological Блесна вращающаяся Jaxon Ratax BO-JXM 2M of IL-35.
Specifically, it is unclear whether single chain IL-12p35 or Ebi3 also possesses intrinsic immune-regulatory activities that can be exploited therapeutically.
In this study, we have produced and used recombinant IL-12p35 rIL-12p35 to directly examine whether IL-12p35 possesses some of the immune-suppressive activities attributed to IL-35 and if it can be used as a biologic to suppress EAE, thereby circumventing the arduous task of bioengineering functional recombinant heterodimeric IL-35 for use in Breg therapy.
All protocols were approved by the NEI Animal Care and Use Committee and followed NIH guidelines for using animals in intramural research.
The IL-12p35 cDNA was cloned into the 3.
To ensure that the recombinant clones expressed bona fide rIL-12p35, we isolated the expression vector HBM-p35-Flag-His from the stable clones and verified by DNA sequencing that no mutations were introduced during cloning or drug selection.
The rIL-12p35 secreted in the insect cell culture was sequentially purified using Ni-NTA Purification system Invitrogensize-exclusion centricon filtration and two consecutive cycles of fast performance liquid chromatography FPLC gel filtration chromatography.
Authenticity of the protein was confirmed by mass spectroscopy.
Induction of EAE Experimental autoimmune encephalomyelitis was induced by subcutaneous immunization with 200 µg myelin oligodendrocyte glycoprotein peptide 35—55 MOG 35—55 Sigma, St.
Louis, MO, USA in CFA emulsion, containing 2.
The mice also received two doses of 200 ng Bordetella pertussis toxin Sigma, St.
Louis, MO, USA on day 0, and day 2 post-immunization intraperitoneally i.
The mice were monitored, and disease severity was assessed daily by a masked observer.
Clinical signs of EAE were graded according to the following scale: 0, no clinical symptoms; 1, clumsiness, incontinence or atonic bladder, flaccid tail; 2, mild paraparesis trouble initiating movement ; 3, moderate paraparesis hind limb weakness ; 4, complete front and hind limb paralysis; 5, moribund state.
For adoptive transfer studies, mice with EAE were sacrificed on day 17 post-immunization and used as donors in passive induction of EAE by adoptive transfer of encephalitogenic cells.
Ten days after adoptive cell transfer, disease was assessed and brain or spinal cord tissue was collected from recipient mice, fixed in 10% buffered formalin and sectioned for histopathological examination.
B cells or T cells were propagated in presence or absence of p35.
After 72 h, cultures were pulsed with 3H-thymidine 0.
Presented data are mean CPM ± SEM of responses of five replicate cultures.
FACS analysis was performed on a MACSQuant analyzer Miltenyi Biotec, San Diego, CA, USA using protein-specific monoclonal antibodies and corresponding isotype control Abs BD Pharmingen, San Diego, CA, USA as described previously .
FACS analysis was performed on samples stained with mAbs conjugated with fluorescent dyes, and each experiment was color-compensated.
Dead cells were stained with dead cell exclusion dye Fixable Viability Dye eFluor ® 450; eBioscienceand live cells were subjected to side scatter and forward scatter analysis.
Quadrant gates were set using isotype controls with less than 0.
Western Blotting Analysis Preparation of whole cell lysates and performance of Western blot analysis were as described previously.
EAE scores were analyzed by nonparametric Mann—Whiney U test two-tailed.
Results IL-12p35 p35 Reduces the Severity of EAE The function of IL-12p35 in vivo is unknown, and loss of IL-12p35 in mouse models of autoimmune disease has produced conflicting results.
This is in part because IL-12p35 is a subunit of IL-12 and IL-35, two IL-12 family cytokines that exert opposite effects on inflammatory responses.
While IL-12p35-deficient mice are protected against collagen-induced arthritisthese mice develop exacerbated EAE.
In this study, we produced the mouse rIL-12p35 and used it to further investigate its potential in vivo functions and to examine whether it might possess intrinsic immune-suppressive effects that can be explored therapeutically.
The rIL-12p35 was produced in insect cells, and the secreted protein was sequentially purified using Ni-NTA Purification system Invitrogensize-exclusion Centricon filtration, and two consecutive cycles of FPLC gel filtration chromatography Figure S1 in Supplementary Material.
These hallmark features of encephalitis were much reduced in mice treated with p35, as indicated by the reduced disease score Figure C.
Analysis of histopathologic sections of the immunized mice revealed substantial infiltration of inflammatory cells into the spinal cord and brain of the untreated mice with EAE compared with a marked reduction of infiltrated inflammatory cells into these tissues of the p35 treatment group Figure B.
IL-12p35 reduced the severity of experimental autoimmune encephalomyelitis EAE induced by active immunization with MOG 35—55.
A Schematic showing the treatment strategy.
White arrows show inflammatory cells in the spinal cord or brain; black arrows denote inflammatory lesions in brain subpial location.
C EAE clinical scores.
D—G Characterization of immune responses on IL-12p35-treated EAE mice.
Both spinal cord and brain cells were collected from individual mice, and the isolated cells were analyzed using FACS.
The data are presented as the mean ± SEM of three determinations.
The recruitment of IL-17-producing Th17 cells, IFN-γ-expressing Th1 lymphocytes as well as several other inflammatory cells of the myeloid lineage into the brain and spinal cord are implicated in the immunopathogenic mechanisms that contribute to MS and EAE .
We therefore isolated cells from the brain and spinal cord and examined whether p35-reduced EAE severity correlated with a reduction of these pathogenic lymphoid and myeloid cell types in the 4 https://aisebijou.ru/100/zerkalo-s-podsvetkoy-belbagno-spc-grt-1000-600-led-btn.html line with our prediction, frequency of pathogenic Th17 and Th1 cells was significantly reduced in both the spinal cord and brain of p35-treated mice compared with untreated mice and interestingly, this was accompanied by increase of IL-10-expressing CD4 + T cells Figures D,E.
Of note, these inflammatory monocyte-derived myeloid cells are rare in normal mice but increase during inflammation, and their disappearance correlates with disease resolution.
Furthermore, diminished recruitment of the inflammatory cells into the brain or spinal cord of the p35-treated mice correlates with reduced expression of CXCR3 Figures F,Gsuggesting that p35 might mitigate EAE, in part, by suppressing trafficking of inflammatory cells into the CNS.
We therefore investigated whether suppression of pathogenic Th17 responses and amelioration of EAE mediated by p35 derived in part from inducing expansion of regulatory cells in the B cell compartment.
Mice were immunized with the MOG 35—55 peptide and treated with p35 or PBS.
Control mice received CFA alone.
Seventeen days post-immunization, cells harvested from the spleen of PBS-treated or p35-treated mice were restimulated in vitro with MOG 35—55 for 72 h.
Intracellular cytokine staining revealed that p35-induced significant expansion of IL-35-producing B cells in the spleen compared with PBS-treated mice Figure A; top panel.
Surprisingly, we also observed significant expansion of IL-35-producing T cells in the spleen of the p35-treated mice Figure A; lower panel.
This observation is consistent with previous studies showing that IL-35 can induce the expansion of a regulatory T cell population that mediates immune suppression via IL-35.
Results of the lymphocyte proliferation assay further show that the increase of these regulatory lymphocyte subsets in the spleen of p35-treated mice correlates with suppression of MOG-specific encephalitogenic T cells Figure B.
IL-12p35 induces expansion of IL-35-expressing B cells in the spleen during experimental autoimmune encephalomyelitis EAE.
Spleen cells isolated from the mice on day 17 after EAE induction were restimulated ex vivo with MOG 35—55 in presence or absence of IL-12p35 for 72 h and were analyzed by intracellular cytokine staining analysis A or lymphocyte proliferation assay B.
A For intracellular cytokine assay, cells were gated on CD19 + or CD4 + cells, and numbers in the quadrants indicate the percentages of T or B cells expressing IL-35 p35 and Ebi3.
The data https://aisebijou.ru/100/zhestkiy-disk-dell-wr712.html presented as the mean ± SEM of three determinations.
B Proliferative responses assessed by 3H-thymidine incorporation assay were analyzed in five replicate cultures, and data presented as mean value of CPM of the five replicate cultures.
Results represent at least three independent experiments.
For this purpose, we isolated cells from the spleen and LN of mice with EAE or from EAE mice that were treated with p35.
As indicated by the EAE clinical scores, cells derived from PBS-treated EAE mice efficiently transferred disease while mice that received cells from p35-treated EAE mice induced significantly milder disease Figure A.
Intracellular cytokine analysis of cells isolated from spinal cord and brain suggested that p35 suppressed the capacity of pathogenic Th1 and Th17 cells to induce EAE by promoting the expansion of IL-10-producing T cells Figures B,C.
We also analyzed the effect of p35 treatment on encephalitogenic cells derived from the spleen and brain by lymphocyte proliferation assay.
The data revealed that the increase of regulatory lymphocyte subsets in the spinal cord, brain, and spleen of the p35-treated mice was accompanied by significant suppression of MOG-specific encephalitogenic cells during EAE Figure D.
Taken together, these results suggest that 4 vivo exposure to p35 can be used to attenuate the pathogenic potential of encephalitogenic T cells, and that this might derive at least in part from the capacity of p35 to induce the expansion of IL-10-producing CD4 + T cells.
IL-12p35 treatment suppressed adoptive transfer of experimental autoimmune encephalomyelitis EAE by encephalitogenic T cells.
Spleen cells from the mice on day 17 after EAE induction were restimulated ex vivo with MOG 35—55 for 72 h.
A EAE clinical scores.
B,C On day 17 after adoptive transfer, cells were isolated from the brain or spinal cord and analyzed by intracellular cytokine staining.
Cells were gated on CD4 + cells, and numbers in quadrants indicate percentage of cells IFN-γ- IL-17- and IL-10-expressing CD4 + T cells.
Five replicate cultures were analyzed, and data presented as mean value of CPM of the five replicate cultures.
The data are presented as the mean ± SEM of three determinations.
IL-6 regulates T cells through activation of STAT3— whereas IL-27 regulates inflammation through activation of STAT1 and STAT3 pathways.
We therefore investigated whether, mechanistically, p35 might have mediated EAE by inhibiting cytokine-induced activation of STAT1 and STAT3 downstream of gp130, a common receptor utilized by both cytokines.
After 72 h, the cells were starved for 2 h in serum-free medium containing 0.
Western blot analysis revealed that unlike the heterodimeric IL-35, p35 could not activate the STAT1 or STAT3 pathway.
Rather, it inhibited activation of both STAT1 and STAT3 pathways Figures A,B.
These observations are in line with a recent study showing that while IL-27p28 by itself Вам Воблер Rapala BX Minnow BXM10 100 мм / 12 гр / Заглубление: 0,9 - 1,5 м / цвет: P где not activate the STAT pathway, it antagonized gp130-mediated signaling.
Western blot analysis of the cells cultured for 3 days also revealed that p35 might also mediate its suppressive activities by antagonizing cell-cycle proteins that regulate lymphocyte proliferation Figure C.
IL-12p35 inhibits STAT signaling pathway and cell-cycle regulatory proteins.
A,B CD4 + T cells were stimulated in anti-CD3 coated plates and with anti-CD28 for 72 h.
The cells were then washed, cultured in serum-free medium with p35 for 2 h, followed by stimulation with IL-6 or IL-27 for the indicated time periods.
C Purified CD4 + T cells were TCR activated for 48 h as described earlier.
Whole cell lysates were analyzed by Western blotting.
Protein levels were normalized to total STAT or β-actin and quantified using Image-J software.
Data are representative of at least three experiments.
IL-12p35 and IL-35 Activate Overlapping and Distinct Immune-Regulatory Mechanisms Although the mechanism s by which IL-35 mediates its biological activities are not fully understood, data provided here suggest that IL-12p35 single chain subunit recapitulate some of the published immune-suppressive effects attributed to IL-35.
However, there are mechanistic differences between IL-12p35 and IL-35 heterodimeric cytokine that derive in part from the fact that IL-35 mediates its biological effects through activation of STAT1 and STAT3 while IL-12p35 could not activate these STAT pathways Figure.
Rather, IL-12p35 seems to function by antagonizing STAT pathways.
Surprisingly, we have uncovered in this study two immune-regulatory molecules, LAG3 and IL-21 receptor IL-21Rthat are differentially expressed by activated B cells in response to IL-35 4 IL-12p35 stimulation Figure.
In contrast to the effects of IL-35 on the expression of LAG3 or IL-21R, culturing CD19 + B cells in medium containing anti-CD40 and p35 had no effect on the percentage of B cells expressing either protein Figure B.
We next examined whether these observations also pertain to B cells activated via T-independent pathway, such as by LPS.
IL-35 but not IL-12p35 induces expansion of LAG3- and IL-21 receptor IL-21R -expressing B cells.
The expression of LAG3 and IL-21R were analyzed with FACS.
After 96 h, we analyzed the expression of LAG3 or IL-21R by FACS.
The data are presented as the mean ± SEM of four determinations.
Data are representative of at least three independent experiments.
Discussion There is increasing awareness that microorganisms and microbial products might be important triggers for autoimmune and chronic inflammatory diseases.
Thus, PAMPs that act through TLRs on DC lead to the production of pro-inflammatory IL-12 4 cytokines as well as suppressive members of the family that guard against excessive immune responses that cause autoimmune pathology.
While these heterodimeric cytokines are under intense investigation, less attention has been given to the physiological functions of the individual single chain proteins that are themselves differentially regulated by pathways downstream of distinct adaptor molecules that mediate transcriptional programs activated by TLRs.
In this study, we have shown that the IL-12p35 subunit protein possesses intrinsic immune-suppressive activities during EAE and can therefore be exploited as a biologic for the treatment of CNS autoimmune diseases.
IL-12p35 suppressed lymphocyte proliferation, antagonized pathogenic Th17 responses, and ameliorated encephalitis in the EAE model by promoting the expansion of Tregs as well as IL-10- and IL-35-producing Breg cells in the brain and spinal cord.
We further show that exposure of pathogenic encephalitogenic T cells to IL-12p35 rendered the cells partially anergic, resulting in diminished capacity to transfer EAE to naïve syngeneic mice.
Importantly, IL-12p35 induced the expansion of IL-10-producing CD4 + T cells in the brain and spinal cord of mice treated with p35.
Thus, p35 treatment recapitulates some of the suppressive effects exhibited by IL-35 in CNS autoimmune diseases.
In context of the mechanism by which IL-12p35 mediates its immune-suppressive activities, we observed some mechanistic difference between IL-12p35 and the heterodimeric IL-35 cytokine.
While IL-35 mediates its biological effects through источник статьи of STAT1, STAT4, and STAT3, IL-12p35 did not activate STAT proteins but instead antagonized STAT pathways induced by IL-6 and IL-27.
These observations are reminiscent of observation reported D-Link DVG-2032S VoIP шлюз IL-27p28, one of the subunits of IL-27.
IL-27p28, independently of Ebi3, antagonized cytokine signaling through gp130.
Notably, IL-27p28 treatment was able to inhibit pathogenic Th1 and Th17 responses and provide protection from EAE as well as from experimental autoimmune uveitis, an autoimmune disease model that shares essential immunological mechanisms with EAE.
Furthermore, mice transgenic for IL-27p28 expression exhibit defects in germinal center formation and Ab production, further supporting the notion that single chain IL-12 family cytokines might possess intrinsic anti-inflammatory activities that can be exploited therapeutically.
It is, however, of note that IL-27 can exert diametrically opposite effects on host immunity deriving from its differential effects on naïve and mature T cells: it promotes the differentiation of naive CD4 + T cells into pathogenic Th1 cells while suppressing production of pro-inflammatory cytokines by mature CD4 + T-helper cells through the induction of IL-10.
Discerning the physiological effects of IL-27 is further complicated by the fact that IL-27 activates both STAT1 and STAT3 in early activated CD4 + T cells while дипломат Diplomate Bleu Parfums парфюм Pour Парфюмерная фам вода мл Femme Paris женщин пур 100 для - activating STAT3 in mature CD4 + T cells.
A consequence of p35-mediated suppression of IL-27-induced activation of STAT1 might be to antagonize the differentiation of naïve T cells into pathogenic Th1 cells during antigen priming while p35-mediated suppression of STAT3 activation might deprive the mature Th17 cell of a transcription factor required for its effector functions.
Thus, p35-induced suppression of Th1 and Th17 cells might in turn increase the frequency of Treg cells.
Another mechanistic difference between IL-12p35 and IL-35 that might be of functional relevance is their differential capacity to induce the expansion of B cells with upregulated expression of LAG3 and IL-21R.
While IL-35 induced the expansion of B cells expressing LAG3 or IL-21R, IL-12p35 could not 4 the expansion of B cells that express these important immune-regulatory proteins that mediate immune tolerance and lymphocyte development.
Although increased expression of LAG3 on T cells is associated with immune suppression, additional studies are required to understand the functional implication of the upregulation of LAG3 on B cells.
Nonetheless, the data showing that IL-35 induced the expansion of B cells with increased expression of IL-21R is intriguing in view of a recent report that functional maturation of IL-10-secreting Breg cells requires IL-21-dependent cognate interactions between B and T cells.
Despite the significant excitement over the possibility of using IL-35 as a biologic for the treatment of autoimmune disease, its therapeutic use should be approached with caution because of the promiscuous chain pairing exhibited by IL-12 family cytokines.
In addition, there is a dearth of pharmacokinetic data on the bioavailability of the IL-35 and the difficulty of ascertaining the stability IL-12p35:Ebi3 complex in vivo.
Unlike IL-12 or IL-23 that are secreted as covalently bound heterodimer of IL-12p35:IL-12p40 or IL-23p19:IL-12p40, the IL-12p35 and Ebi3 subunits are independently secreted and thought to eventually associate under physiological condition and form the stable IL-12p35:Ebi3 complex that exhibits the immune-suppressive functions attributed to the heterodimeric IL-35 cytokine.
Moreover, the factors that promote or regulate the formation and stability of the heterodimer are currently unknown.
While prolonged maintenance of the stable IL-12p35:Ebi3 complex is desirable for treating an autoimmune disease, it also poses the risk of suppressing antitumor immune responses or compromising the efficacy of vaccines against infectious diseases.
Despite the fact that similar concerns can also be raised for the use of IL-12p35, it should be borne in mind that other FDA approved biologics for treatment of MS, such as interferon beta-1b, interferon beta-1a, natalizumab, блог, CoQ10 100 mg 30 капс (California Gold Nutrition) фраза, fingolimod, or daclizumab are associated with adverse effects but are clinically beneficial if used judiciously.
Nonetheless, ease in producing ссылка active IL-12p35 and capacity of the p35 to induce regulatory T and B cells is unique, making IL-12p35 a particularly attractive biologics.
However, production of large amounts of biologically active IL-35 for therapeutic use is difficult and labor intensive, thus providing the major impetus to examine whether the IL-12p35 subunit can recapitulate some of the immunosuppressive activities of IL-35.
Author Contributions JC performed most of the studies.
ID purified and characterized rIL-12p35 and rEbi3, conducted EAE experiments, prepared figures, and edited manuscript.
CH conducted EAE experiments, prepared the figures, and edited the manuscript.
C-RY assisted with FACS analysis.
MM assisted with EAE experiments 4 EAE scoring.
AU assisted with isolation of lymphoid cells; RC provided expertise in analysis of EAE experiments and editing manuscript.
CE conceived, designed, and supervised the project and wrote the manuscript.
Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments The authors thank Rafael Villasmil NEI FLOW Cytometry Core facility and Dr.
Venkat Mohanram Laboratory of Immunology, NEI, NIH for assistance with FACS analysis.
Supplementary Material The Supplementary Material for this article can be found online at.
Schematic representation of the cDNA construct used to produce the recombinant IL-12p35 p35 protein in insect cells.
A HBM, honeybee melittin secretion signal; FLAG and HIS are tags used to facilitate the isolation and purification of the p35 protein.
B,C Characterization of the p35 protein following two sequential purification cycles on fast performance liquid chromatography columns.
D Western blot analysis of the purified p35 protein.
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