Evidence of differential phenotypic plasticity in a desert mustard.

Understanding the effect of the environment on trait variation is critical for ecologically and economically important plants. Here, we asked whether differences in soil moisture are a source of variation in Sahara mustard (Brassica tournefortii). We subjected common garden populations of plants derived from native, invasive, and landrace sources (ranges) to varying water addition treatments. Using principal component analysis, we generated composite variables of life history traits for ANCOVA tests and plotted norms of reaction. Planting time was included as a covariate because we observed differences in seedling emergence despite efforts to standardize germination. We also examined the population coefficient of variation of individual traits (plasticity) and the association of trait CVs with fitness. The amount of plasticity varied but was inconsistent among range sources for all composite traits. Planting time did not affect treatments, but plants from different ranges responded differently to variable planting times. With a surplus of water, plants derived from native and invasive populations plateaued in vegetative trait values but showed a continuous linear increase in reproductive trait values. Possibly as a result of domestication, moderate and high water treatments in landrace plants caused plateaus in composite trait values for flowering phenology, seed count, plant size, and branching. The ecological breadth shown by our plants is likely due to drought tolerance that evolved in Brassica tournefortii source populations.

Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms.

Autoantibodies against leucine-rich glioma inactivated 1 (LGI1) are found in patients with limbic encephalitis and focal seizures. Here, we generate patient-derived monoclonal antibodies (mAbs) against LGI1. We explore their sequences and binding characteristics, plus their pathogenic potential using transfected HEK293T cells, rodent neuronal preparations, and behavioural and electrophysiological assessments in vivo after mAb injections into the rodent hippocampus. In live cell-based assays, LGI1 epitope recognition was examined with patient sera (n = 31), CSFs (n = 11), longitudinal serum samples (n = 15), and using mAbs (n = 14) generated from peripheral B cells of two patients. All sera and 9/11 CSFs bound both the leucine-rich repeat (LRR) and the epitempin repeat (EPTP) domains of LGI1, with stable ratios of LRR:EPTP antibody levels over time. By contrast, the mAbs derived from both patients recognized either the LRR or EPTP domain. mAbs against both domain specificities showed varied binding strengths, and marked genetic heterogeneity, with high mutation frequencies. LRR-specific mAbs recognized LGI1 docked to its interaction partners, ADAM22 and ADAM23, bound to rodent brain sections, and induced internalization of the LGI1-ADAM22/23 complex in both HEK293T cells and live hippocampal neurons. By contrast, few EPTP-specific mAbs bound to rodent brain sections or ADAM22/23-docked LGI1, but all inhibited the docking of LGI1 to ADAM22/23. After intrahippocampal injection, and by contrast to the LRR-directed mAbs, the EPTP-directed mAbs showed far less avid binding to brain tissue and were consistently detected in the serum. Post-injection, both domain-specific mAbs abrogated long-term potentiation induction, and LRR-directed antibodies with higher binding strengths induced memory impairment. Taken together, two largely dichotomous populations of LGI1 mAbs with distinct domain binding characteristics exist in the affinity matured peripheral autoantigen-specific memory pools of individuals, both of which have pathogenic potential. In human autoantibody-mediated diseases, the detailed characterization of patient mAbs provides a valuable method to dissect the molecular mechanisms within polyclonal populations.

Presence, function, and regulation of IL-17F-expressing human CD4+ T cells.

The pro-inflammatory cytokine IL-17A has been implicated in the immunopathology of inflammatory arthritis. IL-17F bears 50% homology to IL-17A and has recently been suggested to play a role in inflammation. We investigated the induction and cytokine profile of IL-17F+ CD4+ T cells, and how IL-17F may contribute to inflammation. Upon culture of healthy donor CD4+ T cells with IL-1ß, IL-23, anti-CD3, and anti-CD28 mAb, both IL-17A and IL-17F-expressing cells were detected. In comparison to IL-17A+ IL-17F- CD4+ T cells, IL-17F+ IL-17A- and IL-17A+ IL-17F+ CD4+ T cells contained lower proportions of IL-10-expressing and GM-CSF-expressing cells and higher proportions of IFN-γ-expressing cells. Titration of anti-CD28 mAb revealed that strong co-stimulation increased IL-17F+ IL-17A- and IL-17A+ IL-17F+ CD4+ T cell frequencies, whereas IL-17A+ IL-17F- CD4+ T cell frequencies decreased. This was partly mediated via an IL-2-dependent mechanism. Addition of IL-17A, IL-17F, and TNF-α to synovial fibroblasts from patients with inflammatory arthritis resulted in significant production of IL-6 and IL-8, which was reduced to a larger extent by combined blockade of IL-17A and IL-17F than blockade of IL-17A alone. Our data indicate that IL-17A and IL-17F are differentially regulated upon T cell co-stimulation, and that dual blockade of IL-17A and IL-17F reduces inflammation more effectively than IL-17A blockade alone.

Phenotypic variation of life-history traits in native, invasive, and landrace populations of Brassica tournefortii.

Varying environments can result in different patterns of adaptive phenotypes. By performing a common greenhouse experiment, we identified phenotypic differentiation on phenology, leaf morphology, branch architecture, size, and reproduction, among native, invasive, and landrace ranges of Brassica tournefortii. We first compared trait means and fitness functions among ranges, then we analyzed how trait means and selection strength of populations respond to varying aridity. Most traits varied such that landrace > invasive > native. Excluding reproduction, which was positively selected, most trait PCs experienced nonlinear selection in the native range but frequently shifted to directional selection in invasive and/or landrace ranges. The absence of strong clines for trait means in landrace and invasive populations suggest that agricultural practices and novel environments in source locations affected adaptive potential. Selection strength on faster reproductive phenology (negative directional) and leaf margin trait (disruptive) PCs coincided with increasing moisture. In native populations, higher aridity was associated with more days to reproduction, but landrace and invasive populations show stable mean time to reproduction with increasing moisture. A stable adaptive trait can increase range expansion in the invasive range, but stability can be beneficial for future harvest of B. tournefortii seed crops in the face of climate change.

Extreme erythrocyte macrocytic and microcytic percentages are highly predictive of morbidity and mortality.

BACKGROUND: The red cell distribution width (RDW) is associated with health outcomes. Whether non-RDW risk information is contained in RBC sizes is unknown. This study evaluated the association of the percentage of extreme macrocytic RBCs (%Macro, RBC volume > 120 fl) and microcytic RBCs (%Micro, RBC volume < 60 fl) and the RDW-size distribution (RDW-sd) with mortality and morbidity. METHODS: Patients (females, n = 165,770; males, n = 100,210) at Intermountain Healthcare were studied if they had a hematology panel between May 2014 and September 2016. Adjusted sex-specific associations of %Macro/%Micro and RDW-sd with mortality and 33 morbidities were evaluated. RESULTS: Among females with fourth-quartile values of %Macro quartile and %Micro (referred to throughout as 4/4), there was an average of 7.2 morbidities versus 2.9 in the lowest risk (LR1) categories, 1/1, 1/2, 2/1, and 2/2 (P < 0.001). Among males, those in the 4/4 category had 8.0 morbidities, while those in the LR1 had 3.4 (P < 0.001). Cox regressions found %Macro/%Micro (4/4 vs. LR1, females: hazard ratio [HR] = 1.97 [95% CI = 1.53, 2.54]; males: HR = 2.17 [CI = 1.72, 2.73]), RDW-sd (quartile 4 vs. 1, females: HR = 1.33 [CI = 1.04, 1.69]; males: HR = 1.41 [CI = 1.10, 1.80]), and RDW (quartile 4 vs. 1, females: HR = 1.59 [CI = 1.26, 2.00]; males: HR = 1.23 [CI = 0.99, 1.52]) independently predicted mortality. Limitations include that the observational design did not reveal causality and unknown confounders may be unmeasured. CONCLUSIONS: Concomitantly elevated %Macro and %Micro predicted the highest mortality risk and the greatest number of morbidities, revealing predictive ability of RBC volume beyond what is measured clinically. Mechanistic investigations are needed to explain the biological basis of these observations. FUNDING: This study was supported by internal Intermountain Heart Institute funds and in-kind support from Sysmex America Inc.

Corrigendum: Geographic population structure in an outcrossing plant invasion after centuries of cultivation and recent founding events.

[This corrects the article DOI: 10.1093/aobpla/ply020.][This corrects the article DOI: 10.1093/aobpla/ply020.].

Geographic population structure in an outcrossing plant invasion after centuries of cultivation and recent founding events.

Population structure and genetic diversity of invasions are the result of evolutionary processes such as natural selection, drift and founding events. Some invasions are also molded by specific human activities such as selection for cultivars and intentional introduction of desired phenotypes, which can lead to low genetic diversity in the resulting invasion. We investigated the population structure, diversity and origins of a species with both accidental and intentional introduction histories, as well as long-term selection as a cultivar. Dyer's woad (Isatis tinctoria; Brassicaceae) has been used as a dye source for at least eight centuries in Eurasia, was introduced to eastern USA in the 1600s, and is now considered invasive in the western USA. Our analyses of amplified fragment length polymorphisms (AFLPs) from 645 plants from the USA and Eurasia did not find significantly lower gene diversity (Hj) in the invaded compared to the native range. This suggests that even though the species was under cultivation for many centuries, human selection of plants may not have had a strong influence on diversity in the invasion. We did find significantly lower genetic differentiation (Fst) in the invasive range but our results still suggested that there are two distinct invasions in the western USA. Our data suggest that these invasions most likely originated from Switzerland, Ukraine and Germany, which correlates with initial biological control agent survey findings. Genetic information on population structure, diversity and origins assists in efforts to control invasive species, and continued combination of ecological and molecular analyses will help bring us closer to sustainable management of plant invasions.

Fab-dsFv: A bispecific antibody format with extended serum half-life through albumin binding.

An antibody format, termed Fab-dsFv, has been designed for clinical indications that require monovalent target binding in the absence of direct Fc receptor (FcR) binding while retaining substantial serum presence. The variable fragment (Fv) domain of a humanized albumin-binding antibody was fused to the C-termini of Fab constant domains, such that the VL and VH domains were individually connected to the Cκ and CH1 domains by peptide linkers, respectively. The anti-albumin Fv was selected for properties thought to be desirable to ensure a durable serum half-life mediated via FcRn. The Fv domain was further stabilized by an inter-domain disulfide bond. The bispecific format was shown to be thermodynamically and biophysically stable, and retained good affinity and efficacy to both antigens simultaneously. In in vivo studies, the serum half-life of Fab-dsFv, 2.6 d in mice and 7.9 d in cynomolgus monkeys, was equivalent to Fab'-PEG.

Can selection on a male mating character result in evolutionary change? A selection experiment on California wild radish, Raphanus sativus.

PREMISE OF THE STUDY: Whenever more pollen grains arrive on stigmas than necessary to fertilize ovules, sexual selection is possible. However, the role of sexual selection remains controversial, in part because of lack of evidence on genetic bases of traits and the response of relevant characters to selection. METHODS: In an experiment with Raphanus sativus, we selected on tendency to sire seeds in the stylar or basal regions of fruits. This character is likely related to pollen tube growth rate, and seed position affects rates of abortion and seed predation. We measured differences among families in seed siring and related characters and evaluated responses to selection. KEY RESULTS: All replicates showed strong effects of pollen donor family on proportion of seeds sired per fruit in mixed pollinations. Most also showed effects of pollen donor family on number of pollen grains per flower and pollen diameter. Two of four replicates showed a response to selection on position of seeds sired. In responding replicates, we found trade-offs in pollen grain size and number; plants with larger pollen grains sired more seeds in the basal region. CONCLUSIONS: Our data suggest a genetic basis for pollen donor ability to sire seeds in competition. The significant response to selection in two replicates shows that position of seeds sired can respond to selection. Thus, all components for sexual selection to occur and affect traits are present. Variation in results among replicates might be due to changes in greenhouse conditions. Environmental effects may contribute to the maintenance of variation in these fitness-related characters.

OX40 blockade inhibits house dust mite driven allergic lung inflammation in mice and in vitro allergic responses in humans.

The costimulatory receptor OX40 is expressed on activated T cells and regulates T-cell responses. Here, we show the efficacy and mechanism of action of an OX40 blocking antibody using the chronic house dust mite (HDM) mouse model of lung inflammation and in vitro HDM stimulation of cells from HDM allergic human donors. We have demonstrated that OX40 blockade leads to a reduction in the number of eosinophils and neutrophils in the lavage fluid and lung tissue of HDM sensitized mice. This was accompanied by a decrease in activated and memory CD4(+) T cells in the lungs and further analysis revealed that both the Th2 and Th17 populations were inhibited. Improved lung function and decreased HDM-specific antibody responses were also noted. Significantly, efficacy was observed even when anti-OX40 treatment was delayed until after inflammation was established. OX40 blockade also inhibited the release of the Th2 cytokines IL-5 and IL-13 from cells isolated from HDM allergic human donors. Altogether, our data provide evidence of a role of the OX40/OX40L pathway in ongoing allergic lung inflammation and support clinical studies of a blocking OX40 antibody in Th2 high severe asthma patients.

Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130-signaling.

Interleukin-6 (IL-6) is a critical regulator of the immune system and has been widely implicated in autoimmune disease. Here, we describe the discovery and characterization of olokizumab, a humanized antibody to IL-6. Data from structural biology, cell biology and primate pharmacology demonstrate the therapeutic potential of targeting IL-6 at "Site 3", blocking the interaction with the signaling co-receptor gp130.

Variation in seedling freezing response is associated with climate in Larrea.

Variation in freezing severity is hypothesized to have influenced the distribution and evolution of the warm desert evergreen genus Larrea. If this hypothesis is correct, performance and survival of species and populations should vary predictably along gradients of freezing severity. If freezing environment changes in the future, the ability of Larrea to adapt will depend on the structure of variation for freezing resistance within populations. To test whether freezing responses vary among and within Larrea populations, we grew maternal families of seedlings from high and low latitude L. divaricata and high latitude L. tridentata populations in a common garden. We measured survival, projected plant area and dark-adapted chlorophyll fluorescence (F (v) /F (m)) before and after cold acclimation and for 2 weeks following a single freeze. We detected significant variation in freezing resistance among species and populations. Maternal family lines differed significantly in their responses to cold acclimation and/or freezing for two out of the three populations: among L. tridentata maternal families and among low latitude L. divaricata maternal families. There were no significant differences across maternal families of high latitude L. divaricata. Our results indicate that increased freezing resistance in high latitude populations likely facilitated historical population expansion of both species into colder climates, but this may have occurred to a greater extent for L. tridentata than for L. divaricata. Differences in the structure of variation for cold acclimation and freezing responses among populations suggest potential differences in their ability to evolve in response to future changes in freezing severity.

Anti-OX40 prevents effector T-cell accumulation and CD8+ T-cell mediated skin allograft rejection.

BACKGROUND: OX40 is a member of the tumor necrosis factor receptor superfamily and is a potent T-cell costimulatory molecule. Although the impact of blockade of the OX40-OX40L pathway has been documented in models of autoimmune disease, the effect on allograft rejection is less well defined. METHODS: The expression of OX40 and impact of OX40 blockade on BM3 T cells (H2Kb-reactive, T-cell receptor-transgenic) after stimulation with alloantigen were assessed in vitro by the incorporation of 3H-thymidine and flow cytometry. In vivo, naïve BM3 or polyclonal CD8+ T cells were transferred into syngeneic recombinase-activating gene(-/-) mice, which received an H2b+ skin allograft with and without anti-OX40. Skin allograft survival was monitored, and the proliferation, number, and phenotype of BM3 T cells were determined using flow cytometry. RESULTS: In vitro allogeneic stimulation of CD8+ T cells resulted in OX40 expression, the blockade of which was found to partially inhibit 3H-thymidine incorporation as a result of increased cell death among activated T cells. Similarly, in vivo, anti-OX40 prevented skin allograft rejection mediated by CD8+ T cells. However, after cessation of anti-OX40 therapy, skin allografts were eventually rejected indicating that tolerance had not been induced. Correlating with the in vitro data, analysis of lymph nodes draining skin allografts revealed that OX40 blockade had no effect on the activation and proliferation of BM3 T cells but rather resulted in diminished effector T-cell accumulation. CONCLUSION: Taken together, these data demonstrate that anti-OX40 attenuates CD8+ T-cell responses to alloantigen by reducing the pool of effector T cells, suggesting that this may be a worthwhile adjunct to preexisting costimulatory molecule-blocking regimens.

Pollen performance of Raphanus sativus (Brassicaceae) declines in response to elevated [CO(2)].

Although increases in atmospheric [CO(2)] are known to affect plant physiology, growth and reproduction, understanding of these effects is limited because most studies of reproductive consequences focus solely on female function. Therefore, we examined the effects of CO(2) enrichment on male function in the annual Raphanus sativus. Pollen donors grown under elevated [CO(2)] initially sired a higher proportion of seeds per fruit than ambient [CO(2)]-grown plants when each was tested against two different standard competitors; however, by the end of the 5-month experiment, these pollen donors sired fewer seeds than ambient [CO(2)]-grown plants and produced a lower proportion of viable pollen grains. The results of this experiment confirm that elevated [CO(2)] can alter reproductive success. Additionally, the change in response to elevated [CO(2)] over time varied among pollen donor families; thus, changes in [CO(2)] could act as a selective force on this species.

The impact of plant and flower age on mating patterns.

BACKGROUND: Over a season, plant condition, amount of ongoing reproduction and biotic and abiotic environmental factors vary. As flowers age, flower condition and amount of pollen donated and received also vary. These internal and external changes are significant for fitness if they result in changes in reproduction and mating. SCOPE: Literature from several fields was reviewed to provide a picture of the changes that occur in plants and flowers that can affect mating over a season. As flowers age, both the entire flower and individual floral whorls show changes in appearance and function. Over a season, changes in mating often appear as alteration in seed production vs. pollen donation. In several species, older, unpollinated flowers are more likely to self. If flowers are receiving pollen, staying open longer may increase the number of mates. In wild radish, for which there is considerable information on seed paternity, older flowers produce fewer seeds and appear to discriminate less among pollen donors. Pollen donor performance can also be linked to maternal plant age. Different pollinators and mates are available across the season. Also in wild radish, maternal plants appear to exert the most control over paternity when they are of intermediate age. CONCLUSIONS: Although much is known about the characters of plants and flowers that can change over a season, there is less information on the effects of age on mating. Several studies document changes in self-pollination over time, but very few, other than those on wild radish, consider more subtle aspects of differential success of pollen donors over time.

Neurodevelopmental outcome of infants with unilateral or bilateral periventricular hemorrhagic infarction.

OBJECTIVE: Periventricular hemorrhagic infarction (PVHI) is a major contributing factor to poor neurodevelopmental outcomes in preterm infants. We hypothesized that surviving infants with unilateral PVHI would have more favorable outcomes than those with bilateral PVHI. METHODS: This was a multicenter, retrospective study of infants who were admitted to 3 NICUs in North Carolina from 1998 to 2004. The clinical course and late neuroimaging studies and neurodevelopmental outcomes of 69 infants who weighed <1500 g and had confirmed PVHI on early cranial ultrasonography were reviewed. A predictive model for Bayley Scales of Infant Development, Second Edition, Mental Developmental Index (MDI) <70 was constructed by using radiologic and clinical variables. RESULTS: Infants with unilateral PVHI had higher median MDI (82 vs 49) and Psychomotor Developmental Index (53 vs 49) than infants with bilateral PVHI. Infants with unilateral PVHI were less likely to have severe cerebral palsy (adjusted odds ratio: 0.15 [95% confidence interval (CI): 0.05-0.45]) than infants with bilateral PVHI. Infants who had unilateral PVHI and developed periventricular leukomalacia and retinopathy of prematurity that required surgery had an increased probability of having MDI <70 compared with those without these complications (probability of MDI <70: 89% [95% CI: 0.64-1.00] vs 11% [95% CI: 0.01-0.28]). CONCLUSIONS: Infants with unilateral PVHI had better motor and cognitive outcomes than infants with bilateral PVHI. By combining laterality of PVHI, periventricular leukomalacia, and retinopathy of prematurity it is possible to estimate the probability of having an MDI <70, which will assist clinicians when counseling families.

A short treatment with an antibody to sclerostin can inhibit bone loss in an ongoing model of colitis.

Chronic inflammation leads to bone loss, and increased fracture rates have been reported in a number of human chronic inflammatory conditions. The study reported here investigates the skeletal effects of dosing a neutralizing antibody to the bone regulatory protein sclerostin in a mouse model of chronic colitis. When dosed prophylactically, an antibody to sclerostin (Scl-AbI) did not reduce the weight loss or histological changes associated with colitis but did prevent inflammation-induced bone loss. At the end of the experiment, Scl-AbI-treated animals had a significantly higher femoral BMD (+27%, p < 0.05) than control antibody (Cntrl-Ab)-treated animals. In a second experiment, treatment with Scl-AbI was delayed until colitis had developed, by which time the mechanical properties of femurs in colitic animals were significantly worse than those of healthy age-matched control mice (maximum load, -26%, p < 0.05; energy, -37%, p < 0.05; ultimate strength, -33%, p < 0.05; elastic modulus, -17%, p < 0.05). A short treatment with Scl-AbI halted bone loss and reversed the decline of both intrinsic and extrinsic mechanical properties of the femur such that, after 19 days of treatment, the bone mechanical properties in the Scl-AbI-treated animals were not significantly different from those of noncolitic age-matched controls. Serum markers of bone formation and resorption suggested that the antibody to sclerostin stimulated osteoblast activity and inhibited osteoclast-mediated bone resorption.

Hyperglycemia predicts mortality after CABG: postoperative hyperglycemia predicts dramatic increases in mortality after coronary artery bypass graft surgery.

OBJECTIVE: Risk of morbidity and mortality after coronary artery bypass graft surgery (CABG) is higher in patients with clinical diabetes mellitus (DM). We evaluated whether outcomes are affected by postoperative hyperglycemia in CABG patients independent of preoperative DM diagnosis. RESEARCH DESIGN AND METHODS: A total of 2297 consecutive CABG patients were studied. The first glucose value after surgery completion (mean 15 min) was tested as a predictor of outcome. Primary outcome variables were prolonged ventilation (>24 h), deep sternal wound infection, renal failure, permanent stroke, any reoperation, length of stay (>14 days) and mortality. All outcomes except for prolonged ventilation and length of stay were tracked out to 30 days postoperatively. Patients were stratified by glycemic control: Low (glucose <80), normal (referent, glucose 80-110), high (glucose 111-200) and very high (glucose >200 mg/dl). Multivariable logistic regression was used to determine the independent predictive value of glycemic groups, adjusted for outcome specific risk scores from the Society of Thoracic Surgeons model. RESULTS: Patient distribution among groups low through very high were 44 (1.9%), 476 (20.7%), 1425 (62.0%) and 352 (15.3%). Greater complication rates were noted in the very high group when compared with the referent group: prolonged ventilation (adjusted odds ratio (OR)=2.66, P<.001), length of stay >14 days (adjusted OR=2.06, P=.004) and mortality (adjusted OR=7.71, P<.001). CONCLUSION: Patients with blood glucose values >200 mg/dl immediately after CABG had an increased risk of complications, including mortality, independent of a clinical diagnosis of DM. This study documents the high risk associated with early postoperative hyperglycemia in this group, suggesting the need for prospective trials of glycemic control.

Effects of pollen load size on seed paternity in wild radish: the roles of pollen competition and mate choice.

For sexual selection to be important in plants, it must occur at pollen load sizes typical of field populations. However, studies of the impact of pollen load size on pollen competition have given mixed results, perhaps because so few of these studies directly examined the outcome of mating when pollen load size was varied. We asked whether seed paternity after mixed pollination of wild radish was affected by pollen load sizes ranging from 22 to 220 pollen grains per stigma. We examined the seed siring abilities of 12 pollen donors across 11 maternal plants. Seed paternity was statistically indistinguishable across the pollen load sizes even though, overall, the pollen donors sired different numbers of seeds. This lack of effect of pollen load size on seed paternity may have occurred because fruit abortion and early abortion or failure of fertilization of seeds increased as load size decreased. Thus, failures of fruits and seeds sired by poorer pollen donors may keep seed paternity constant across pollen load sizes.

Blockade of colony stimulating factor-1 (CSF-I) leads to inhibition of DSS-induced colitis.

BACKGROUND: Intestinal inflammation associated with inflammatory bowel disease (IBD) is typically characterized by an inflammatory cell infiltrate and pro-inflammatory cytokine production. Of particular interest, the frequency of colony stimulating factor-1 (CSF-l)-expressing cells is increased in active lesions. In this study, we have investigated the role of CSF-1 in mucosal inflammation, using a murine model of colitis induced by dextran sulfate sodium (DSS). METHODS: A neutralizing anti-CSF-1 antibody was administered to Balb/c mice that received DSS in their drinking water. Signs of colitis, such as clinical disease score, cellular infiltrate, and cytokine production, were assessed. RESULTS: Administration of a neutralizing anti-CSF-1 antibody significantly inhibited DSS-induced colitis. Clinical symptoms, such as weight loss and the appearance of diarrhea or fecal blood, were reduced by CSF-1 blockade; histologic scores were also improved. The cellular infiltrate of macrophages and T cells was inhibited and a trend toward reduced production of pro-inflammatory cytokines was noted. CONCLUSIONS: This is the first study to demonstrate that CSF-1 plays an important role in mediating intestinal mucosal inflammation and therefore may prove to be an attractive therapeutic target for intestinal diseases such as inflammatory bowel disease.