Cytochrome P450 Family 46 Subfamily A Member 1 Promotes the Progression of Colorectal Cancer by Inducing Tumor Cell Proliferation and Angiogenesis.

BACKGROUND/AIM: Cytochrome P450 family 46 subfamily A member 1 (CYP46A1) has been implicated in the development and progression of various cancers. This study aimed to analyze the expression of CYP46A1, examining its relationship with oncogenic behaviors, and determining its prognostic implications in colorectal cancer (CRC). MATERIALS AND METHODS: A total of 225 patients with CRC who underwent curative surgical resection were examined using paraffin-embedded tissue blocks and subjected to tumor-specific survival analysis. The expression of CYP46A1 was assessed in CRC tissues through reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. The CRC cells' apoptosis, proliferation, angiogenesis, and lymphangiogenesis were analyzed using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays, alongside immunohistochemical staining for Ki-67, CD34, and D2-40 antibodies. RESULTS: CYP46A1 expression was found to be up-regulated in CRC tissues compared to normal colorectal mucosa. Such expression was significantly associated with advanced stage, deeper tumor invasion, lymph node metastasis, distant metastasis, and decreased survival. Furthermore, the mean Ki-67 labeling index and microvessel density values in CYP46A1-positive tumors were significantly elevated compared to CYP46A1-negative tumors. However, there was no discernible correlation between CYP46A1 expression and either the apoptotic index or lymphatic vessel density value. CONCLUSION: CYP46A1 promotes CRC progression, specifically through the induction of tumor cell proliferation and angiogenesis. The insights provided may hold potential implications for future therapeutic interventions targeting CYP46A1.

Small-cell Neuroendocrine Carcinoma of the Extrahepatic Bile Duct: A Rare Case Report.

Neuroendocrine carcinoma (NEC) arising from the extrahepatic bile duct is extremely rare and commonly mistaken for cholangiocarcinoma. Therefore, NEC of the bile duct is difficult to diagnose preoperatively. Previously reported cases were resected with a diagnosis of cholangiocarcinoma and diagnosed with NEC after surgery. This paper reports an 84-year-old female with small-cell NEC of the extrahepatic bile duct, confirmed by a biopsy from an ERCP, with a review of the relevant literature. Contrast-enhanced abdomen computed tomography and magnetic resonance cholangiopancreatography revealed an approximately 1.7 cm enhancing intraductal mass in the proximal common bile duct with dilatation of the upstream bile duct. ERCP showed a long strictured segment in the proximal common bile duct with bile duct dilatation. A biopsy was performed at the site of the stricture. Histological examinations and hematoxylin-eosin staining showed the solid proliferation of small tumor cells with irregularly shaped hyperchromatic nuclei. Immunohistochemical examinations showed that the tumor cells were positive for CD56 and synaptophysin. Small-cell NEC of the extrahepatic bile duct was confirmed based on the histology and immunohistochemistry findings. The patient and their family denied treatment because of the patient's old age.

Clinical Outcome and Risk Factors of Chronic Radiation Proctitis Following Pelvic Radiation Therapy.

BACKGROUND/AIM: Pelvic radiation therapy (RT) is a common treatment for malignancies, including gynecological, genitourinary, and lower gastrointestinal tract cancers. However, chronic radiation proctitis (RP) is an unavoidable side effect, and its clinical presentation varies from asymptomatic to potentially life-threatening. This study evaluated the clinical characteristics and risk factors of chronic RP. PATIENTS AND METHODS: Patients with chronic RP (212) following RT for various pelvic cancers between January 2015 and December 2021 were enrolled. Clinical characteristics of RP were analyzed retrospectively. Severity was graded according to the Radiation Therapy Oncology Group (RTOG) modified rectal toxicity score and Vienna rectoscopy score (VRS), and risk factors were statistically analyzed. RESULTS: The most common pelvic cancer observed was cervical cancer. The patients received three-dimensional conformal RT (3D-CRT), intensity-modulated RT, or a combination of 3D-CRT and intracavitary RT (ICR). Rectal bleeding occurred in 70 (33.0%) patients. Previous abdominopelvic surgery and total radiation dose significantly correlated with the RTOG score and VRS. Previous abdominopelvic surgery, ICR, and total radiation dose were associated with chronic hemorrhagic RP. All patients with chronic hemorrhagic RP were treated with argon plasma coagulation (APC). 91.4% of cases required 1-3 APC sessions to resolve the bleeding, with a mean of 1.7 sessions. CONCLUSION: Our results showed that previous abdominopelvic surgery and total radiation dose were significant risk factors related to chronic RP, while total radiation dose was related to chronic hemorrhagic RP. We also showed that APC was effective and safe for chronic hemorrhagic RP.

CD47 mediates the progression of colorectal cancer by inducing tumor cell apoptosis and angiogenesis.

CD47 is an immunoregulatory protein that is found on the cell surface and plays significant roles in cellular functions such as proliferation, apoptosis, migration, and immune homeostasis. CD47 is overexpressed in various human cancers and is associated with tumor development, progression, and poor prognosis. In this study, we analyzed the expression of CD47 to determine whether it affected the oncogenic behavior of colorectal cancer (CRC) and investigated the prognostic value of CD47 expression in patients with CRC. We investigated 468 patients with CRC who underwent curative surgery and examined the expression of CD47 in tumor and lymph node tissues by performing RT-PCR and immunohistochemistry. Apoptosis, proliferation, angiogenesis, and lymphangiogenesis were determined via a TUNEL assay and immunohistochemical staining for Ki-67, CD34, and D2-40. CD47 expression was increased in human CRC tumors and metastatic lymph nodes compared with normal colorectal mucosa and non-metastatic lymph node tissues. CD47 expression was significantly associated with perineural invasion, lymphovascular invasion, cell differentiation, cancer stage, depth of invasion, lymph node metastasis, distant metastasis, and poor survival. The mean apoptotic index and microvessel density value of CD47-positive tumors were significantly higher than those of CD47-negative tumors. However, no significant difference was observed between CD47 expression and Ki-67 labeling index or lymphatic vessel density. These results indicate that CD47 mediated the progression of CRC by inducing tumor cell apoptosis and angiogenesis.

Primary Esophageal Malignant Melanoma in Korea: Clinical features, Management and Prognosis.

Primary esophageal melanoma is a rare disease with a poor prognosis. To date, 18 cases have been reported in Korea. Four patients visited the Chonnam National University Hwasun Hospital with dysphagia, followed by epigastric pain and discomfort, odynophagia, and weight loss. Esophagogastroduodenoscopy revealed a black pigmented polypoid mass, protruding mass, or black-pigmented flat lesions. Two patients had distant metastases and lymphadenopathies in imaging studies. Two patients underwent esophagectomy and intrathoracic esophagogastrostomy. One patient was treated with chemotherapy and interferon-alpha. The other patient declined further treatment. The routine histology using H&E revealed brown-colored atypical melanocytes. Immunohistochemical staining exhibited strong reactivity for Melan-A, S-100, and HMB-45 proteins. The biopsy specimens were interpreted to be malignant melanoma. One patient had multiple distant metastases 13 months after surgery. The other patient had no recurrence for 33 months after surgery. The patient treated with chemotherapy and interferon-alpha showed disease progression in the follow-up examination. Primary esophageal melanoma in Korea is a rare disease characterized by aggressive behavior, early metastasis, and poor prognosis.

Case report of gastric syphilis in Korea: Clinical features, pathology, management, and prognosis.

RATIONALE: Syphilis is a contagious infectious disease caused by Treponema pallidum. Gastric involvement of syphilis is rare and has nonspecific gastrointestinal symptoms and endoscopic findings. To date, 16 cases have been reported in Korea. Here, we report 2 additional cases of gastric syphilis in men in their 30 second. PATIENTS CONCERNS: Two 35- and 33-year-old men presented with epigastric pain. DIAGNOSIS: The serum venereal disease research laboratory and fluorescent treponemal antibody absorption tests were positive. Esophagogastroduodenoscopy showed multiple variable-sized flat elevated lesions and geographic ulcers with whitish exudates in the antrum and body. Warthin-Starry silver staining of endoscopic biopsy specimens confirmed gastric syphilis. INTERVENTIONS: The patients were treated with an intramuscular injection of 2.4 million units of benzathine penicillin once a week for 3 weeks. OUTCOMES: Clinical symptoms and gastric lesions were completely resolved. LESSONS: First, gastric syphilis, despite its rarity and nonspecific symptoms and endoscopic findings, should be considered in a rare extracutaneous presentation of syphilis. Second, a high index of clinical suspicion and an accurate diagnosis based on a combination of clinical, radiological, endoscopic, serologic, and histopathologic findings provide an opportunity to identify and treat patients with gastric syphilis.

Predictors of clinical outcomes of self-expandable metal stent treatment for malignant colorectal obstruction: A Honam Association for the Study of Intestinal Disease (HASID) multicenter study.

ABSTRACT: There has been increased use of self-expandable metal stents (SEMS) in treating malignant colorectal obstruction (MCO). The aim of this study was to investigate factors that are associated with the outcomes of SEMS placement for MCO.Clinical data from patients who underwent SEMS placement for MCO at 6 hospitals in Honam province of South Korea between 2009 and 2018 were reviewed retrospectively. Eight hundred two patients were identified and their data were analyzed. Technical success, clinical success, complications, and predictors of outcome were included as main outcome measures.Technical and clinical success rates were 98.8% (792/802) and 90.1% (723/802), respectively. Complications including stent migration, stent occlusion due to tumor ingrowth and outgrowth, perforation, bacteremia/fever, and bleeding occurred in 123 (15.3%) patients. In multivariate regression analyses, procedure time was significantly associated with the technical success of SEMS placement (P = .001). Longer length of obstruction, the use of covered stent, and longer procedure time were significant independent predictive factors for the clinical success of SEMS placement (odds ratio [OR] 0.974 (95% confidence interval [CI] 0.950-0.990); P = .043, OR 0.255 (95% CI 0.138-0.471); P < .001, and OR 0.957 (95% CI 0.931-0.984); P = .002, respectively). Stage IV colorectal cancer and the use of covered stent were significant independent predictive factors for the development of complications after SEMS placement (OR 2.428 (95% CI 1.407-4.188); P = .001 and OR 3.329 (95% CI 2.060-5.378); P < .001, respectively).Longer length of obstruction, the use of covered stent, and longer procedure time were associated with lower clinical success rates. Having stage IV colorectal cancer and the use of covered stents were associated with an increased risk of complications.

Targeting the myeloid checkpoint receptor SIRPα potentiates innate and adaptive immune responses to promote anti-tumor activity.

BACKGROUND: Signal regulatory protein α (SIRPα) is a myeloid-lineage inhibitory receptor that restricts innate immunity through engagement of its cell surface ligand CD47. Blockade of the CD47-SIRPα interaction synergizes with tumor-specific antibodies and T-cell checkpoint inhibitors by promoting myeloid-mediated antitumor functions leading to the induction of adaptive immunity. Inhibition of the CD47-SIRPα interaction has focused predominantly on targeting CD47, which is expressed ubiquitously and contributes to the accelerated blood clearance of anti-CD47 therapeutics. Targeting SIRPα, which is myeloid-restricted, may provide a differential pharmacokinetic, safety, and efficacy profile; however, SIRPα polymorphisms and lack of pan-allelic and species cross-reactive agents have limited the clinical translation of antibodies against SIRPα. Here, we report the development of humanized AB21 (hAB21), a pan-allelic anti-SIRPα antibody that binds human, cynomolgus monkey, and mouse SIRPα alleles with high affinity and blocks the interaction with CD47. METHODS: Human macrophages derived from donors with various SIRPα v1 and v2 allelic status were used to assess the ability of hAB21 to enhance phagocytosis. HAB21_IgG subclasses were evaluated for targeted depletion of peripheral blood mononuclear cells, phagocytosis and in vivo efficacy in xenograft models. Combination therapy with anti-PD1/anti-PD-L1 in several syngeneic models was performed. Immunophenotyping of tissues from MC38 tumor-bearing mice treated with AB21 and anti-PD-1 was evaluated. PK, PD and tolerability of hAB21 were evaluated in cynomolgus monkeys. RESULTS: SIRPα blockade with hAB21 promoted macrophage-mediated antibody-dependent phagocytosis of tumor cells in vitro and improved responses to rituximab in the Raji human tumor xenograft mouse model. Combined with PD-1/PD-L1 blockade, AB21 improved response rates by facilitating monocyte activation, dendritic cell activation, and T cell effector functions resulting in long term, durable antitumor immunity. In cynomolgus monkeys, hAB21 has a half-life of 5.3 days at 10 mg/kg and complete target occupancy with no hematological toxicity or adverse findings at doses up to 30 mg/kg. CONCLUSIONS: The in vitro and in vivo antitumor activity of hAB21 broadly recapitulates that of CD47 targeted therapies despite differences in ligand expression, binding partners, and function, validating the CD47-SIRPα axis as a fundamental myeloid checkpoint pathway and its blockade as promising therapeutic intervention for treatment of human malignancies.

Preclinical Efficacy and Safety Comparison of CD3 Bispecific and ADC Modalities Targeting BCMA for the Treatment of Multiple Myeloma.

The restricted expression pattern of B-cell maturation antigen (BCMA) makes it an ideal tumor-associated antigen (TAA) for the treatment of myeloma. BCMA has been targeted by both CD3 bispecific antibody and antibody-drug conjugate (ADC) modalities, but a true comparison of modalities has yet to be performed. Here we utilized a single BCMA antibody to develop and characterize both a CD3 bispecific and 2 ADC formats (cleavable and noncleavable) and compared activity both in vitro and in vivo with the aim of generating an optimal therapeutic. Antibody affinity, but not epitope was influential in drug activity and hence a high-affinity BCMA antibody was selected. Both the bispecific and ADCs were potent in vitro and in vivo, causing dose-dependent cell killing of myeloma cell lines and tumor regression in orthotopic myeloma xenograft models. Primary patient cells were effectively lysed by both CD3 bispecific and ADCs, with the bispecific demonstrating improved potency, maximal cell killing, and consistency across patients. Safety was evaluated in cynomolgus monkey toxicity studies and both modalities were active based on on-target elimination of B lineage cells. Distinct nonclinical toxicity profiles were seen for the bispecific and ADC modalities. When taken together, results from this comparison of BCMA CD3 bispecific and ADC modalities suggest better efficacy and an improved toxicity profile might be achieved with the bispecific modality. This led to the advancement of a bispecific candidate into phase I clinical trials.

ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile.

CD47 is a widely expressed cell surface protein that functions as an immune checkpoint in cancer. When expressed by tumor cells, CD47 can bind SIRPα on myeloid cells, leading to suppression of tumor cell phagocytosis and other innate immune functions. CD47-SIRPα signaling has also been implicated in the suppression of adaptive antitumor responses, but the relevant cellular functions have yet to be elucidated. Therapeutic blockade of the CD47 pathway may stimulate antitumor immunity and improve cancer therapy. To this end, a novel CD47-blocking molecule, ALX148, was generated by fusing a modified SIRPα D1 domain to an inactive human IgG1 Fc. ALX148 binds CD47 from multiple species with high affinity, inhibits wild type SIRPα binding, and enhances phagocytosis of tumor cells by macrophages. ALX148 has no effect on normal human blood cells in vitro or on blood cell parameters in rodent and non-human primate studies. Across several murine tumor xenograft models, ALX148 enhanced the antitumor activity of different targeted antitumor antibodies. Additionally, ALX148 enhanced the antitumor activity of multiple immunotherapeutic antibodies in syngeneic tumor models. These studies revealed that CD47 blockade with ALX148 induces multiple responses that bridge innate and adaptive immunity. ALX148 stimulates antitumor properties of innate immune cells by promoting dendritic cell activation, macrophage phagocytosis, and a shift of tumor-associated macrophages toward an inflammatory phenotype. ALX148 also stimulated the antitumor properties of adaptive immune cells, causing increased T cell effector function, pro-inflammatory cytokine production, and a reduction in the number of suppressive cells within the tumor microenvironment. Taken together, these results show that ALX148 binds and blocks CD47 with high affinity, induces a broad antitumor immune response, and has a favorable safety profile.

RN927C, a Site-Specific Trop-2 Antibody-Drug Conjugate (ADC) with Enhanced Stability, Is Highly Efficacious in Preclinical Solid Tumor Models.

Trop-2, also known as TACSTD2, EGP-1, GA733-1, and M1S1, is frequently expressed on a variety of human carcinomas, and its expression is often associated with poor prognosis of the diseases. However, it is also present on the epithelium of several normal tissues. A comprehensively designed Trop-2-targeting antibody-drug conjugate (ADC), balancing both efficacy and toxicity, is therefore necessary to achieve clinical utility. To this end, we developed a cleavable Trop-2 ADC (RN927C) using a site-specific transglutaminase-mediated conjugation method and a proprietary microtubule inhibitor (MTI) linker-payload, PF-06380101. Robust in vitro cytotoxicity of RN927C was observed on a panel of Trop-2-expressing tumor cell lines, with IC50 generally in the subnanomolar range. As expected for an MTI-containing ADC, RN927C readily induced mitotic arrest of treated cells in vitro and in vivo, followed by subsequent cell death. The in vivo efficacy of RN927C was tested in multiple cell line and patient-derived xenograft tumor models, including pancreatic, lung, ovarian, and triple-negative breast tumor types. Single-dose administration of RN927C at 0.75 to 3 mg/kg was generally sufficient to induce sustained regression of Trop-2-expressing tumors and showed superior efficacy over standard treatment with paclitaxel or gemcitabine. Administration of RN927C in nonhuman primate toxicity studies resulted in target-mediated effects in skin and oral mucosa, consistent with Trop-2 expression in these epithelial tissues with minimal, non-dose limiting off-target toxicities. On the basis of the combined efficacy and safety results, RN927C is postulated to have a favorable therapeutic index for treatment of solid tumors. Mol Cancer Ther; 15(11); 2698-708. ©2016 AACR.

Morphing technique reveals intact perception of object motion and disturbed perception of emotional expressions by low-functioning adolescents with Autism Spectrum Disorder.

A morphing procedure has been designed to compare directly the perception of emotional expressions and of moving objects. Morphing tasks were presented to 12 low-functioning teenagers with Autism Spectrum Disorder (LF ASD) compared to 12 developmental age-matched typical children and a group presenting ceiling performance. In a first study, when presented with morphed stimuli of objects and emotional faces, LF ASD showed an intact perception of object change of state together with an impaired perception of emotional facial change of state. In a second study, an eye-tracker recorded visual exploration of morphed emotional stimuli displayed by a human face and a robotic set-up. Facing the morphed robotic stimuli, LF ASD displayed equal duration of fixations toward emotional regions and toward mechanical sources of motion, while the typical groups tracked the emotional regions only. Altogether the findings of the two studies suggest that individuals with ASD process motion rather than emotional signals when facing facial expressions.

Decreased maternal and fetal cholesterol following maternal bococizumab (anti-PCSK9 monoclonal antibody) administration does not affect rat embryo-fetal development.

Bococizumab is a humanized monoclonal IgG2Δa antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) for the treatment of hyperlipidemia. The evaluation of potential effects on embryo-fetal development was conducted in the rat. In a pharmacokinetic/pharmacodynamic study bococizumab was administered intravenously to pregnant Sprague-Dawley (SD) rats (n = 8/group) at 0, 10, 30, and 100 mg/kg during organogenesis. Maternal and fetal bococizumab, total cholesterol and HDL concentrations were determined. Bococizumab was well tolerated and there were no effects on ovarian or uterine parameters. Maternal and fetal bococizumab exposure increased with increasing dose, with a corresponding dose-dependent decrease in fetal cholesterol levels. Maternal cholesterol levels were decreased significantly, with reductions that were of a similar magnitude regardless of dose. In the definitive embryo-fetal development study bococizumab was administered to pregnant SD rats (n = 20/group) at 0, 10, 30, and 100 mg/kg and no adverse maternal or developmental effects were observed up to 100 mg/kg. These studies have provided an appropriate and relevant safety assessment of bococizumab in pregnant rats to inform human risk assessment, demonstrating no adverse effects on embryo-fetal development at magnitudes greater than anticipated clinical exposure and in the presence of maximal reductions in maternal cholesterol and dose-dependent reductions in fetal cholesterol.

Formation, clearance, deposition, pathogenicity, and identification of biopharmaceutical-related immune complexes: review and case studies.

Vascular inflammation, infusion reactions, glomerulopathies, and other potentially adverse effects may be observed in laboratory animals, including monkeys, on toxicity studies of therapeutic monoclonal antibodies and recombinant human protein drugs. Histopathologic and immunohistochemical (IHC) evaluation suggests these effects may be mediated by deposition of immune complexes (ICs) containing the drug, endogenous immunoglobulin, and/or complement components in the affected tissues. ICs may be observed in glomerulus, blood vessels, synovium, lung, liver, skin, eye, choroid plexus, or other tissues or bound to neutrophils, monocytes/macrophages, or platelets. IC deposition may activate complement, kinin, and/or coagulation/fibrinolytic pathways and result in a systemic proinflammatory response. IC clearance is biphasic in humans and monkeys (first from plasma to liver and/or spleen, second from liver or spleen). IC deposition/clearance is affected by IC composition, immunomodulation, and/or complement activation. Case studies are presented from toxicity study monkeys or rats and indicate IHC-IC deposition patterns similar to those predicted by experimental studies of IC-mediated reactions to heterologous protein administration to monkeys and other species. The IHC-staining patterns are consistent with findings associated with generalized and localized IC-associated pathology in humans. However, manifestations of immunogenicity in preclinical species are generally not considered predictive to humans.

Characterization, biomarkers, and reversibility of a monoclonal antibody-induced immune complex disease in cynomolgus monkeys (Macaca fascicularis).

Two 6-month repeat-dose toxicity studies in cynomolgus monkeys illustrated immune complex-mediated adverse findings in individual monkeys and identified parameters that potentially signal the onset of immune complex-mediated reactions following administration of RN6G, a monoclonal antibody (mAb). In the first study, 3 monkeys exhibited nondose-dependent severe clinical signs accompanied by decreased erythrocytes with increased reticulocytes, neutrophilia, monocytosis, thrombocytopenia, coagulopathy, decreased albumin, azotemia, and increased serum levels of activated complement products, prompting unscheduled euthanasia. Histologically, immunohistochemical localization of RN6G was associated with monkey immunoglobulin and complement components in glomeruli and other tissues, attributable to immune complex disease (ICD). All 3 animals also had anti-RN6G antibodies and decreased plasma levels of RN6G. Subsequently, an investigational study was designed and conducted with regulatory agency input to detect early onset of ICD and assess reversibility to support further clinical development. Dosing of individual animals ceased when biomarkers of ICD indicated adverse findings. Of the 12 monkeys, 1 developed anti-RN6G antibodies and decreased RN6G exposure that preceded elevations in complement products, interleukin-6, and coagulation parameters and decreases in albumin and fibrinogen. All findings in this monkey, except for antidrug antibody (ADA), reversed after cessation of dosing without progressing to adverse sequelae typically associated with ICD.

Intermittent oral coadministration of a gamma secretase inhibitor with dexamethasone mitigates intestinal goblet cell hyperplasia in rats.

Dexamethasone was given in 2 oral dosing regimens with repeat dose oral administration of the gamma secretase inhibitor (GSI), PF-03084014, in Sprague-Dawley (SD) rats in order to evaluate the effects of coadministration of dexamethasone on GSI-induced goblet cell hyperplasia (GCH) in the intestinal tract. Safety end points were evaluated in 1 week and 1 month studies. The dosing regimens tested in the 1-month studies included a 1-week pretreatment with 1.0 mg/kg dexamethasone followed by a 3-week repeat dose treatment with 100 mg/kg GSI or concurrent intermittent treatment with 1.0 mg/kg dexamethasone on weeks 1 and 3 and repeat dose treatment with 100 mg/kg GSI for 4 weeks. Pretreatment with dexamethasone for 1 week transiently mitigated the severity of intestinal GCH for up to 1 week. Intermittent coadministration of dexamethasone on weeks 1 and 3 with GSI repeat dosing for 4 weeks mitigated intestinal GCH for up to 4 weeks post treatment. Treatment-related morbidity and mortality occurred on day 7 with 150 mg/kg GSI and 5 mg/kg dexamethasone coadministration, and on days 13, 14, and 23 with 100 mg/kg GSI and 1 mg/kg dexamethasone coadministration.

Anti-IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function.

Genetic variation in the IL-7 receptor-α (IL-7R) gene is associated with susceptibility to human type 1 diabetes (T1D). Here we investigate the therapeutic efficacy and mechanism of IL-7Rα antibody in a mouse model of T1D. IL-7Rα antibody induces durable, complete remission in newly onset diabetic mice after only two to three injections. IL-7 increases, whereas IL-7Rα antibody therapy reduces, the IFN-γ-producing CD4(+) (T(H)1) and IFN-γ-producing CD8(+) T cells. Conversely, IL-7 decreases and IL-7Rα antibody enhances the inhibitory receptor Programmed Death 1 (PD-1) expression in the effector T cells. Programmed Death 1 blockade reversed the immune tolerance mediated by the IL-7Rα antibody therapy. Furthermore, IL-7Rα antibody therapy increases the frequency of regulatory T cells without affecting their suppressor activity. The durable efficacy and the multipronged tolerogenic mechanisms of IL-7Rα antibody therapy suggest a unique disease-modifying approach to T1D.

IL-7 promotes T(H)1 development and serum IL-7 predicts clinical response to interferon-ß in multiple sclerosis.

The interleukin-7 receptor α chain (IL-7Rα) gene was identified as a top non-major histocompatibility complex-linked risk locus for multiple sclerosis (MS). Recently, we showed that a T helper 1 (T(H)1)-driven, but not a T(H)17-driven, form of MS exhibited a good clinical response to interferon-ß (IFN-ß) therapy. We now demonstrate that high serum levels of IL-7, particularly when paired with low levels of IL-17F, predict responsiveness to IFN-ß and hence a T(H)1-driven subtype of MS. We also show that although IL-7 signaling is neither necessary nor sufficient for the induction or expansion of T(H)17 cells, IL-7 can greatly enhance both human and mouse T(H)1 cell differentiation. IL-7 alone is sufficient to induce human T(H)1 differentiation in the absence of IL-12 or other cytokines. Furthermore, targeting IL-7/IL-7Rα is beneficial in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Mice treated with IL-7Rα-blocking antibodies before or after onset of paralysis exhibited reduced clinical signs of EAE, with reduction in peripheral naïve and activated T cells, whereas central memory T, regulatory T, B, and natural killer cell populations were largely spared. IL-7Rα antibody treatment markedly reduced lymphocyte infiltration into the central nervous system in mice with EAE. Thus, a serum profile of high IL-7 may signify a T(H)1-driven form of MS and may predict outcome in MS patients undergoing IFN-ß therapy. Blockade of IL-7 and the IL-7Rα pathway may have therapeutic potential in MS and other autoimmune diseases.

The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation.

The vanilloid receptor TRPV1 (transient receptor potential vanilloid 1) is a cation channel that serves as a polymodal detector of pain-producing stimuli such as capsaicin, protons (pH <5.7), and heat. TRPV1 antagonists block pain behaviors in rodent models of inflammatory, neuropathic, and cancer pain, suggesting their utility as analgesics. Here, we report that TRPV1 antagonists representing various chemotypes cause an increase in body temperature (hyperthermia), identifying a potential issue for their clinical development. Peripheral restriction of antagonists did not eliminate hyperthermia, suggesting that the site of action is predominantly outside of the blood-brain barrier. Antagonists that are ineffective against proton activation also caused hyperthermia, indicating that blocking capsaicin and heat activation of TRPV1 is sufficient to produce hyperthermia. All TRPV1 antagonists evaluated here caused hyperthermia, suggesting that TRPV1 is tonically activated in vivo and that TRPV1 antagonism and hyperthermia are not separable. TRPV1 antagonists caused hyperthermia in multiple species (rats, dogs, and monkeys), demonstrating that TRPV1 function in thermoregulation is conserved from rodents to primates. Together, these results indicate that tonic TRPV1 activation regulates body temperature.