Disease Activity In Mice Research Articles

Intermittent fasting attenuates cognitive dysfunction and systemic disease activity in mice with neuropsychiatric systemic lupus erythematosus

AimsCognitive dysfunction and systemic disease activity are common manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE), a condition that affects a patient's health and quality of life. Clinical and preclinical studies have demonstrated that intermittent fasting (IF) improves health conditions and quality of life. Therefore, we aimed to test whether IF improves cognitive dysfunction and systemic disease activities in mice with NPSLE and to examine the underlying mechanisms. Main methodsNPSLE-prone MRL/lpr mice underwent 8 weeks of alternate-day fasting or ad libitum feeding, followed by behavioral tests to assess cognitive manifestations and biochemical tests to evaluate systemic disease activities. Key findingsIF significantly improved cognitive functionality, decreased blood-brain barrier permeability, and reduced the activation of astrocytes and microglia in the hippocampi of MRL/lpr mice. IF also improved systemic disease activities, including reduced kidney glomerular injury and interstitial inflammation, peripheral blood autoantibody titer, and splenic T lymphocyte contents. Mechanistic studies demonstrated that IF attenuates cognitive dysfunction by facilitating the microglial transition to the M2-like phenotype via the AMPK/PPARγ/NF-κB pathway. SignificanceTogether, observations from this study suggest a potential therapeutic benefit of IF in the treatment of cognitive dysfunction in patients with NPSLE.

An Intestinal Microbiome Intervention Affects Biochemical Disease Activity in Patients with Antiphospholipid Syndrome.

Background The origin of autoantibodies in patients with antiphospholipid syndrome (APS) is unknown. The gut microbiome contributes to autoimmunity and contains peptide homologues to the main APS autoantigen, which affect disease activity in animal models. Alteration of the gut microbiota with vancomycin diminishes disease activity in mice but no data on the effect of gut microbiota alteration in APS patients are available to date. Objective To evaluate whether the gut microbiome affects disease activity in human APS. Methods This was a pre-post design intervention study in APS patients with stable disease and no gastrointestinal comorbidity. Subjects received oral vancomycin, 500 mg four times daily for 7 days, previously shown to alter gut microbiota composition without systemic effects. Disease activity was assessed at four time points by measuring a panel of clinical phenotype-related biomarkers: antiphospholipid antibodies (APLAs), complement and inflammation markers, and hemostatic parameters. The primary outcome was the composite of the biomarker panel determined by multilevel principal component analysis. Results A total of 15 subjects completed the study. The primary outcome, the first principal component of the biomarker panel data, was significantly different after 7 days of vancomycin treatment ( p = 0.03), but not at day 42. APLA titers were unaffected. Unexpectedly, 4 out of 15 patients were negative for APLAs at baseline. In a post-hoc analysis, there was a prolonged effect for subjects with positive antibodies at baseline ( p = 0.03). In subjects with negative APLAs at baseline, the intervention showed no effect. Conclusion The intestinal microbiome affects the biochemical disease activity in APS patients. The mechanism is yet unknown but appears to be APS-specific.

JAK2/STAT5 inhibition protects mice from experimental autoimmune encephalomyelitis by modulating T cell polarization

Multiple sclerosis (MS) has been considered as a T cell-mediated autoimmune disease. However, the signaling pathways regulating effector T cells in MS have yet to be elucidated. Janus kinase 2 (JAK2) plays a crucial role in hematopoietic/immune cytokine receptor signal transduction. Here, we tested the mechanistic regulation of JAK2 and the therapeutic potential of pharmacological JAK2 inhibition in MS. Both inducible whole-body JAK2 knockout and T cell-specific JAK2 knockout completely prevented the onset of experimental autoimmune encephalomyelitis (EAE), a widely used MS animal model. Mice with JAK2 deficiency in T cells exhibited minimal demyelination and minimal CD45+ leukocyte infiltration in the spinal cord, accompanied by a remarkable reduction of T helper cell type 1 (TH1) and type 17 (TH17) in the draining lymph nodes and spinal cord. In vitro experiments showed that disruption of JAK2 markedly suppressed TH1 differentiation and IFNγ production. The phosphorylation of signal transducer and activator of transcription 5 (STAT5) was reduced in JAK2 deficient T cells, while STAT5 overexpression significantly increased TH1 and IFNγ production in STAT5 transgenic mice. Consistent with these results, JAK1/2 inhibitor baricitinib or selective JAK2 inhibitor fedratinib attenuated the frequencies of TH1 as well as TH17 in the draining lymph nodes and alleviated the EAE disease activity in mice. Our findings suggest that overactive JAK2 signaling in T lymphocytes is the culprit in EAE, which may serve as a potent therapeutic target for autoimmune disease.

Therapeutic Approaches Targeting miRNA in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a potentially fatal systemic autoimmune disease, and its etiology involves both genetic and environmental factors such as sex hormone imbalance, genetic predisposition, epigenetic regulation, and immunological factors. Dysregulation of microRNA (miRNA) is suggested to be one of the epigenetic factors in SLE. miRNA is a 22-nucleotide single-stranded noncoding RNA that contributes to post-transcriptional modulation of gene expression. miRNA targeting therapy has been suggested to be useful for the treatment of cancers and other diseases. Gene knockout and miRNA targeting therapy have been demonstrated to improve SLE disease activity in mice. However, these approaches have not yet reached the level of clinical application. miRNA targeting therapy is limited by the fact that each miRNA has multiple targets. In addition, the expression of certain miRNAs may differ among cell tissues within a single SLE patient. This limitation can be overcome by targeted delivery and chemical modifications. In the future, further research into miRNA chemical modifications and delivery systems will help us develop novel therapeutic agents for SLE.

Antcin K inhibits VCAM-1-dependent monocyte adhesion in human rheumatoid arthritis synovial fibroblasts.

BackgroundAntcin K, an extract of Antrodia cinnamomea (a medicinal mushroom endemic to Taiwan commonly used in Chinese medicine preparations), inhibits proinflammatory cytokine production and angiogenesis in human rheumatoid arthritis synovial fibroblasts (RASFs), major players in RA disease. Antcin K also inhibits disease activity in mice with collagen-induced arthritis (CIA). Up until now, the effects of Antcin K upon cell adhesion molecules (CAMs) were unknown.MethodsRA and healthy synovial tissue samples (n = 10 in each group) were retrieved from the Gene Expression Omnibus (GEO) database (accession code: GDS5401) to compare CAM and monocyte marker expressions. In addition, synovial tissue samples from six RA patients and six patients undergoing arthroscopy for trauma/joint derangement (healthy controls) were subjected to immunohistochemical (IHC) analysis. mRNA and protein expression levels were analyzed in RASFs using RT-qPCR (Reverse transcription-quantitative polymerase chain reaction) and Western blot. RASFs were incubated with Antcin K and examined for monocyte adherence by fluorescence microscopy. Ankle joint tissue specimens from a CIA mouse model and healthy controls were stained with hematoxylin and eosin (H&E) and Safranin-O/Fast Green to examine histological changes and evidence of bone loss. IHC analysis determined levels of vascular cell adhesion molecule 1 (VCAM-1) and CD11b in CIA ankle tissue and clinical synovial tissue.ResultsLevels of VCAM-1 expression were higher in the GEO database specimens and the study’s clinical samples of RA synovial tissue compared with the healthy specimens. Antcin K dose-dependently inhibited VCAM-1 expression and monocyte adhesion in RASFs. Antcin K also significantly inhibited levels of VCAM-1 and monocyte CD11b expression in CIA tissue. These effects appeared to be mediated by MEK1/2-ERK, p38, and AP-1 signaling.ConclusionsAntcin K seems promising for the treatment of RA and deserves further investigations.

PET Imaging of System xC - in Immune Cells for Assessment of Disease Activity in Mice and Patients with Inflammatory Bowel Disease.

We aimed to explore whether the imaging of antiporter system xC - of immune cells with (4S)-4-(3-18F-fluoropropyl)-l-glutamate (18F-FSPG) PET can assess inflammatory bowel disease (IBD) activity in murine models and patients (NCT03546868). Methods: 18F-FSPG PET imaging was performed to assess IBD activity in mice with dextran sulfate sodium-induced and adoptive T-cell transfer-induced IBD and a cohort of 20 patients at a tertiary care center in South Korea. Immunohistochemical analysis of system xC - and cell surface markers was also studied. Results: Mice with experimental IBD showed increased intestinal 18F-FSPG uptake and xCT expression in cells positive (+) for CD11c, F4/80, and CD3 in the lamina propria, increases positively associated with clinical and pathologic disease activity. 18F-FSPG PET studies in patients, most of whom were clinically in remission or had mildly active IBD, showed that PET imaging was sufficiently accurate in diagnosing endoscopically active IBD and remission in patients and bowel segments. 18F-FSPG PET correctly identified all 9 patients with superficial or deep ulcers. Quantitative intestinal 18F-FSPG uptake was strongly associated with endoscopic indices of IBD activity. The number of CD68+xCT+ and CD3+xCT+ cells in 22 bowel segments from patients with ulcerative colitis and the number of CD68+xCT+ cells in 7 bowel segments from patients with Crohn disease showed a significant positive association with endoscopic indices of IBD activity. Conclusion: The assessment of system xC - in immune cells may provide diagnostic information on the immune responses responsible for chronic active inflammation in IBD. 18F-FSPG PET imaging of system xC - activity may noninvasively assess the IBD activity.

Mastiha (Pistacia lentiscus) Improves Gut Microbiota Diversity, Hepatic Steatosis, and Disease Activity in a Biopsy-Confirmed Mouse Model of Advanced Non-Alcoholic Steatohepatitis and Fibrosis.

ScopeAs a result of the obesity epidemic, the prevalence of non‐alcoholic steatohepatitis (NASH) is increasing. No drug is approved for the treatment of NASH. In this study, the effect of a nutritional supplement, Mastiha or Chios mastic gum, on metabolic and histological parameters and on the gut microbiome in mice with NASH and fibrosis was investigated.Methods and resultsAdvanced NASH was induced by feeding C57BL/6J mice a diet rich in fat, sucrose, and cholesterol for 41 weeks. After randomization, animals received the NASH‐inducing diet with or without 0.2% (w/w) Mastiha for a further 8 weeks. Disease activity was assessed by liver histology and determination of plasma transaminase activities. Fecal microbiota DNA extraction and 16S rRNA amplicon sequencing were used to determine the composition of the gut microbiome.Mastiha supplementation led to a significant reduction in circulating alanine aminotransferase (ALT) activity, improvement in hepatic steatosis and collagen content, and a reduction in NAFLD activity score. Furthermore, it resulted in a partial but significant recovery of gut microbiota diversity and changes in identity and abundance of specific taxa.ConclusionThis is the first study demonstrating an improvement in disease activity in mice with advanced NASH with fibrosis by a diet containing Mastiha.

A New Approach for the Treatment of Arthritis in Mice with a Novel Conjugate of an Anti-C5aR1 Antibody and C5 Small Interfering RNA.

Rheumatoid arthritis (RA) is an inflammatory autoimmune joint disease in which the complement system plays an important role. Of the several components of complement, current evidence points to C5 as the most important inducer of inflammation. Several groups generated Abs or small interfering RNAs (siRNAs) or small molecule inhibitors against C5 and C5aR1 (CD88) that have showed some efficacy in RA in animal models. However, none of these candidate therapeutics has moved from bench to bedside. In this study, we test in collagen Ab-induced arthritis (CAIA) a new therapeutic strategy using a novel anti-C5ab-C5 siRNA conjugate. We first demonstrate that although C5aR2 or C5L2 (GPR77) plays no role in CAIA, C5aR1 contributes to pathogenesis. We demonstrate that injection of siRNAs blocking C5, C5aR1, or the combination decreased clinical disease activity in mice with CAIA by 45%, 51%, and 58%, respectively. Anti-C5 Ab (BB5.1) has only limited efficacy, but significantly reduced arthritis up to 66%. We then generated a novel anti-C5aR1 Ab-protamine-C5 siRNA conjugate. To our knowledge, we show for the first time that whereas unconjugated Ab plus siRNAs reduce arthritis by 19%, our anti-C5aR1 Ab-protamine-C5 siRNA conjugate was effective in reducing arthritis by 83% along with a parallel decrease in histopathology, C3 deposition, neutrophils, and macrophages in the joints of mice with CAIA. These data suggest that by targeting anti-C5 siRNAs to the receptor for its C5a activation fragment (C5aR1), a striking clinical effect can be realized.

Alpha-melanocyte stimulating hormone ameliorates disease activity in an induced murine lupus-like model

Alpha-melanocyte stimulating hormone (α-MSH) is a neuropeptide exhibiting anti-inflammatory activity in experimental models of autoimmune diseases. However, no studies thus far have examined the effects of α-MSH on systemic lupus erythematosus (SLE). This study aimed to determine the effects of an α-MSH agonist in induced murine lupus. Here we employed female Balb/cAn mice in which lupus was induced by pristane. Groups of lupus animals were treated daily with the α-MSH analogue [Nle4, DPhe7]-α-MSH (NDP-MSH) (1·25 mg/kg) injected intraperitoneally or saline for 180 days. Normal animals comprised the control group. Arthritis incidence, plasma immunoglobulin (Ig)G isotypes, anti-nuclear antibodies (ANA) and plasma cytokines were evaluated. Renal function was assessed by proteinuria and histopathological lesion. Glomerular levels of IgG, α-smooth muscle actin (α-SMA), inducible nitric oxide synthase (iNOS), C3, CD3, melanocortin receptors (MCR)1, corticotrophin-releasing factor (CRF) and α-MSH was estimated by immunohistochemistry. When compared with normal controls, lupus animals exhibited increased arthritis, IgG levels, ANA, interleukin (IL)-6, IL-10, proteinuria and mesangial cell proliferation together with glomerular expression of α-SMA and iNOS. Glomerular expression of MCR1 was reduced in lupus animals. NDP-MSH treatment reduced arthritis scores by 70% and also diminished IgG1 and IgG2a levels and ANA incidence. In the glomerulus, NDP-MSH treatment reduced cellularity by 50% together with reducing IgG deposits, and expression levels of α-SMA, iNOS and CRF were also all decreased. Taken together, our results suggest for the first time that α-MSH treatment improves several parameters of SLE disease activity in mice, and indicate that this hormone is an interesting potential future treatment option.

Human neutrophil peptide-1 aggravates dextran sulfate sodium-induced colitis

Human neutrophil peptide (HNP)-1, HNP-2, and HNP-3 (HNP-1-3) are useful biomarkers for ulcerative colitis (UC). The precise roles of these peptides in UC are poorly understood, however. The aim of this study was to determine whether HNP-1 affects disease activity in mice with experimental colitis. Experimental colitis was induced in BALB/c or severe combined immunodeficiency (SCID) mice using dextran sulfate sodium (DSS). Mice were subsequently treated intraperitoneally with HNP-1 (100 μg/day) or phosphate-buffered saline (PBS) from day 4 to day 6. The severity of colitis was evaluated based on a disease activity index, histologic score, and cytokine expression. Body weight and colon length significantly decreased and the disease activity index score, histologic score, and myeloperoxidase activity significantly increased in HNP-1-treated BALB/c mice compared with PBS-treated mice. Interferon-γ and tumor necrosis factor-α levels in colon culture supernatants-derived HNP-1-treated mice were also significantly higher, and interleukin (IL)-1β levels tended to increase in response to HNP-1. In addition, treating SCID mice with HNP-1 aggravated DSS-induced colitis and IL-1β levels in colon culture supernatants from these mice were significantly higher than in cultures obtained from control mice. Furthermore, in both BALB/c and SCID mice increased recruitment of F4/80-positive macrophages was observed in the inflamed colonic mucosa following HNP-1 injections. High concentrations of HNP-1 aggravate DSS-induced colitis, including upregulated expression of such macrophage-derived cytokines as IL-1β. These results indicate that high concentrations of HNP-1-3 in patients with UC may exacerbate disease activity via increased cytokine production.

Mesenchymal Stem Cells Derived from Human Gingiva Are Capable of Immunomodulatory Functions and Ameliorate Inflammation-Related Tissue Destruction in Experimental Colitis

Aside from the well-established self-renewal and multipotent differentiation properties, mesenchymal stem cells exhibit both immunomodulatory and anti-inflammatory roles in several experimental autoimmune and inflammatory diseases. In this study, we isolated a new population of stem cells from human gingiva, a tissue source easily accessible from the oral cavity, namely, gingiva-derived mesenchymal stem cells (GMSCs), which exhibited clonogenicity, self-renewal, and multipotent differentiation capacities. Most importantly, GMSCs were capable of immunomodulatory functions, specifically suppressed peripheral blood lymphocyte proliferation, induced expression of a wide panel of immunosuppressive factors including IL-10, IDO, inducible NO synthase (iNOS), and cyclooxygenase 2 (COX-2) in response to the inflammatory cytokine, IFN-gamma. Cell-based therapy using systemic infusion of GMSCs in experimental colitis significantly ameliorated both clinical and histopathological severity of the colonic inflammation, restored the injured gastrointestinal mucosal tissues, reversed diarrhea and weight loss, and suppressed the overall disease activity in mice. The therapeutic effect of GMSCs was mediated, in part, by the suppression of inflammatory infiltrates and inflammatory cytokines/mediators and the increased infiltration of regulatory T cells and the expression of anti-inflammatory cytokine IL-10 at the colonic sites. Taken together, GMSCs can function as an immunomodulatory and anti-inflammatory component of the immune system in vivo and is a promising cell source for cell-based treatment in experimental inflammatory diseases.

Low Dietary Calcium Levels Modulate Mucosal Caspase Expression and Increase Disease Activity in Mice with Dextran Sulfate Sodium–Induced Colitis 3

Dietary calcium (Ca) positively modulates the susceptibility to colon cancer, but its effects on related or earlier colonic pathologies, such as inflammation and mucosal dysregulation, are poorly understood. We tested the effects of differing dietary Ca levels on acute dextran sulfate sodium (DSS)-induced colitis in mice. BALB/c mice received a normal Ca (NCa) diet (0.5% Ca), a high Ca (HCa) diet (1.5% Ca), a low Ca (LCa) diet (0.05% Ca), or a very low Ca (VLCa) diet (0.009% Ca) for 3 wk. Mucosal caspases 1, 3, and 9 were assessed by Western blotting, and the histological crypt score was assessed by microscopy. Half of the mice in each group received DSS (1.5%) for 20 d in their drinking water, and disease activity was assessed. Increasing or lowering dietary Ca increased mucosal caspases (P < 0.0001 vs. NCa). Crypt scores increased with decreasing dietary Ca levels (P < 0.0001, r = −0.675), indicating that elevated caspases in LCa groups reflected early subclinical inflammation. DSS-induced disease activity was higher in mice fed low dietary Ca levels [P < 0.0001, VLCa and DSS vs. NCa and DSS (NCaDSS) and P < 0.005, LCa and DSS vs. NCaDSS], and mice from the VLCa group were moribund within 11 d of DSS administration. Those in the HCa group did not differ greatly from controls. Together, these data indicate that Ca protects against DSS-induced colitis in mice. The mechanisms are unclear, but the calcium-sensing receptor and/or luminal precipitates of calcium phosphate microparticles may be involved. Whether these observations can be extended to patients with colitis or infectious diarrhea deserves consideration.

Signal Transducer and Activator of Transcription 5b Promotes Mucosal Tolerance in Pediatric Crohn's Disease and Murine Colitis

Growth hormone (GH) regulates anabolic metabolism via activation of the STAT5b transcription factor and reduces mucosal inflammation in colitis. Peroxisome proliferator-activated receptor (PPAR) gamma suppresses mucosal inflammation and is regulated by GH through STAT5b. We hypothesized that the GH:STAT5b axis influences susceptibility to colitis via regulation of local PPARgamma abundance. Colon biopsies from children with newly diagnosed Crohn's disease (CD) and controls were exposed to GH in short-term organ culture. Trinitrobenzene sulfonic acid (TNBS) administration was used to induce colitis in STAT5b-deficient mice and wild-type controls, with and without rosiglitazone pretreatment. GH receptor, STAT5b, PPARgamma, and nuclear factor kappaB activation and expression were determined. Epithelial cell GH receptor expression and GH-dependent STAT5b activation and PPARgamma expression were reduced in CD colon. STAT5b-deficient mice exhibited reduced basal PPARgamma nuclear abundance and developed more severe proximal colitis after TNBS administration. This was associated with a significant increase in mucosal nuclear factor kappaB activation at baseline and after TNBS administration. Rosiglitazone ameliorated colitis in wild-type mice but not STAT5b-deficient mice. GH-dependent STAT5b activation is impaired in affected CD colon and contributes to chronic mucosal inflammation via down-regulation of local PPARgamma expression. Therapeutic activation of the GH:STAT5b axis therefore represents a novel target for restoring both normal anabolic metabolism and mucosal tolerance in CD.

Reversal of experimental colitis disease activity in mice following administration of an adenoviral IL-10 vector

Genetic deficiency in the expression of interleukin-10 (IL-10) is associated with the onset and progression of experimental inflammatory bowel disease (IBD). The clinical significance of IL-10 expression is supported by studies showing that immune-augmentation of IL-10 prevents inflammation and mucosal damage in animal models of colitis and in human colitis. Interleukin-10 (IL-10), an endogenous anti-inflammatory and immunomodulating cytokine, has been shown to prevent some inflammation and injury in animal and clinical studies, but the efficacy of IL-10 treatment remains unsatisfactory. We found that intra-peritoneal administration of adenoviral IL-10 to mice significantly reversed colitis induced by administration of 3% DSS (dextran sulfate), a common model of colitis. Adenoviral IL-10 (Ad-IL10) transfected mice developed high levels of IL-10 (394 +/- 136 pg/ml) within the peritoneal cavity where the adenovirus was expressed. Importantly, when given on day 4 (after the induction of colitis w/DSS), Ad-IL10 significantly reduced disease activity and weight loss and completely prevented histopathologic injury to the colon at day 10. Mechanistically, compared to Ad-null and DSS treated mice, Ad-IL10 and DSS-treated mice were able to suppress the expression of MAdCAM-1, an endothelial adhesion molecule associated with IBD. Our results suggest that Ad-IL10 (adenoviral IL-10) gene therapy of the intestine or peritoneum may be useful in the clinical treatment of IBD, since we demonstrated that this vector can reverse the course of an existing gut inflammation and markers of inflammation.

The non-thiol angiotensin-converting enzyme inhibitor quinapril suppresses inflammatory arthritis.

In addition to its vasoactive effects, angiotensin II has proinflammatory properties. Angiotensin-converting enzyme (ACE) inhibitors reduce the production of angiotensin II and could therefore act as anti-inflammatory agents. Here we investigated the capacity of the ACE inhibitor quinapril to modulate inflammatory arthritis. We studied the effect of quinapril on disease activity in mice with collagen-induced arthritis (CIA). Mice received oral quinapril (10 mg/kg/day) at the time of arthritis induction (prophylaxis protocol) or at the onset of mild arthritis (therapy protocol). Concentrations of immunoglobulin G (IgG) subtypes specific for bovine Type II collagen and TNF-alpha were measured by enzyme-linked immunoassay. Quinapril significantly diminished the activity of CIA when given as prophylaxis or therapy (prophylaxis protocol, P<0.001; therapy protocol P=0.002). Antigen-specific IgG2a antibodies were reduced by 52% (P=0.02) in the quinapril prophylaxis protocol. Suppression of arthritis by quinapril was associated with reduced articular expression of TNF-alpha by 68% (P=0.01) in the prophylaxis protocol and 27% (P=0.06) in the therapy protocol. Quinapril therapy also inhibited expression of splenocyte TNF-alpha production following lipopolysaccharide (LPS) in vitro stimulation by 59% (P=0.02). In parallel human in vitro experiments, ACE inhibition suppressed LPS-stimulated production of TNF-alpha by monocytes. In order to confirm that the action of quinapril occurred predominantly through suppression of angiotensin II, parallel experiments with the angiotensin receptor antagonist candesartan cilexetil demonstrated that this agent also inhibited disease activity in CIA. These data suggest that angiotensin II is a mediator of chronic inflammation and that ACE inhibition may have therapeutic effects in human inflammatory arthritis.

Biologic properties and therapeutic potential of glucagon-like peptide-2.

Glucagon-like peptide-2 (GLP-2), a 33 amino acid, proglucagon-derived peptide with intestinotrophic activity, is secreted from enteroendocrine cells in the small and large intestine. This review describes recent advances in our understanding of GLP-2 physiology from rodent experiments in vivo. GLP-2 administration induces mucosal epithelial proliferation in small and large bowel and stomach. GLP-2 is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP-IV) to produce the biologically inactive form GLP-2(3-33), however, GLP-2 analogs that confer resistance to DPP-IV exhibit enhanced biologic activity in vivo. GLP-2-treated bowel retains normal to enhanced functional absorptive capacity. Furthermore, GLP-2 infusion prevents total parenteral nutrition (TPN)-associated intestinal hypoplasia, and enhances bowel adaptation and nutrient absorption in rats following small bowel resection. GLP-2 also reverses weight loss and improves histologic and biochemical parameters of disease activity in mice with experimental colitis. GLP-2 is an intestine-derived peptide with intestinotrophic properties that may be therapeutically useful in diseases characterized by intestinal damage or insufficiency.

The activity of dipeptidyl peptidase II and dipeptidyl peptidase IV in mice immunized with type II collagen

We investigated the activity of peptidases in the serum of mice with experimental polyarthritis that was induced by the injection of type II collagen, an experimental model of human rheumatoid arthritis. The activity of dipeptidyl peptidase II (DPP II) was increased and that of dipeptidyl peptidase IV (DPP IV) was decreased resulting in the significant increase of the serum DPP II/DPP IV ratio in the polyarthritic mice compared with that of controls. These results indicate that the DPP II/DPP IV ratio is a novel index of disease activity in mice with collagen-induced polyarthritis and may be useful in assessing the activity of rheumatoid arthritis in humans.