Background/Aims: This study assessed the efficacy and safety of adalimumab (ADA) and explored predictors of response in Korean patients with ulcerative colitis (UC). Methods: A prospective, observational, multicenter study was conducted over 56 weeks in adult patients with moderately to severely active UC who received ADA. Clinical response, remission, and mucosal healing were assessed using the Mayo score. Results: A total of 146 patients were enrolled from 17 academic hospitals. Clinical response rates were 52.1% and 37.7% and clinical remission rates were 24.0% and 22.0% at weeks 8 and 56, respectively. Mucosal healing rates were 39.0% and 30.1% at weeks 8 and 56, respectively. Prior use of anti-tumor necrosis factor-α (anti-TNF-α) did not affect clinical and endoscopic responses. The ADA drug level was significantly higher in patients with better outcomes at week 8 (P<0.05). In patients with lower endoscopic activity, higher body mass index, and higher serum albumin levels at baseline, the clinical response rate was higher at week 8. In patients with lower Mayo scores and C-reactive protein levels, clinical responses, and mucosal healing at week 8, the clinical response rate was higher at week 56. Serious adverse drug reactions were identified in 2.8% of patients. Conclusions ADA is effective and safe for induction and maintenance in Korean patients with UC, regardless of prior anti-TNF-α therapy. The ADA drug level is associated with the efficacy of induction therapy. Patients with better short-term outcomes were predictive of those with an improved long-term response.

BACKGROUND: The prevalence of acute kidney injury (AKI) in elderly patients has grown considerably. Age-associated changes in the immune system can be one of the critical factors determining AKI outcomes. This study aimed to investigate the role of senescence of bone marrow (BM)-derived cells in the development of AKI, focusing on the immune response. METHODS: Female 7-week-old C57BL/6 mice were irradiated and treated with BM cells from either 48-week-old or 8-week-old male mice. Ischemia-reperfusion injury (IRI) was induced, and their functional deterioration, histological tubular damage, and inflammatory responses were compared. For the in-vitro study, lipopolysaccharide (LPS)-stimulated cytokine production by BM cells from old and young mice were examined. RESULTS: At 24 hours after IRI, there was no significant difference in the number of circulating immune cells between the mice transplanted with old or young BM cells. However, the mice with old BM cells showed less functional deterioration and histological tubular injury than those with young BM cells. Moreover, macrophage infiltration and renal cytokine interleukin (IL)-12 levels were lower in the mice with old BM cells at 24 hours post-IRI. Consistently, the in vitro study showed that LPS-induced production of cytokines interferon-γ, monocyte chemoattractant protein-1, and IL-10 was attenuated in cultured old BM cells, suggesting that age-related functional changes in these cells may lead to reduced inflammation in IRI. CONCLUSION: Immunosenescence could affect the susceptibility and response to renal IRI. Further studies specifically addressing age-related alterations can help in the development of treatment strategies for elderly patients with AKI.
Acute Kidney Injury ; Aged ; Aging ; Animals ; Bone Marrow Cells ; Bone Marrow ; Chemokine CCL2 ; Cytokines ; Female ; Humans ; Immune System ; Immunosenescence ; In Vitro Techniques ; Inflammation ; Interleukin-10 ; Interleukins ; Macrophages ; Male ; Mice ; Prevalence ; Reperfusion Injury

Regulatory T (Treg) cells are a distinct subset of CD4⁺ T cells. Instead of triggering adaptive immunity, they suppress immune responses. Small numbers of Treg cells reside within lymphoid organs and peripheral tissues, but their contribution to immune tolerance is so significant that defects in Treg cell function cause catastrophic immune disorders. Since they were first discovered 20 years ago, efforts have been made to understand the differences in developmental processes between Treg cells and conventional T cells that determine the ultimate fate of the overall T-cell population. Transcription factor Foxp3 is crucial for Treg cell differentiation, but it is not the whole story. Owing to recent advances in Treg cell research, we are now on the verge of appreciating the comprehensive mechanisms underlying Treg cell generation. Here, we discuss major discoveries, active study topics and remaining questions regarding Treg cell development.

We present a case of a 65-year-old man with psoriasis who developed autoimmune hepatitis (AIH) without receiving immunosuppressive therapy with either anti-tumor necrosis factor-α or methotrexate. The AIH had completely resolved at 2 months after prednisolone and azathioprine therapy. This case confirms the need to consider AIH in psoriasis patients who experience new elevations in liver enzymes. To our knowledge, this is first description of the development of AIH in an immunosuppressant-naïve patient with psoriasis.
Aged ; Azathioprine ; Hepatitis, Autoimmune* ; Humans ; Liver ; Methotrexate ; Necrosis ; Prednisolone ; Psoriasis*

Effective clearance of inflammatory cells is required for resolution of inflammation. Here, we show in vivo evidence that apoptosis and reverse transendothelial migration (rTEM) are important mechanisms in eliminating neutrophils and facilitating recovery following ischemia/reperfusion injury (IRI) of the kidney. The clearance of neutrophils was delayed in the Bax knockout (KO)BM → wild-type (WT) chimera in which bone marrow derived cells are partially resistant to apoptosis, compared to WTBM → WT mice. These mice also showed delayed functional, histological recovery, increased tissue cytokines, and accelerated fibrosis. The circulating intercellular adhesion molecule-1 (ICAM-1)+ Gr-1+ neutrophils displaying rTEM phenotype increased during the recovery phase and blockade of junctional adhesion molecule-C (JAM-C), a negative regulator of rTEM, resulted in an increase in circulating ICAM-1+ neutrophils, faster resolution of inflammation and recovery. The presence of Tamm-Horsfall protein (THP) in circulating ICAM-1+ neutrophils could suggest that they are derived from injured kidneys. In conclusion, we suggest that apoptosis and rTEM are critically involved in the clearance mechanisms of neutrophils during the recovery phase of IRI.
Acute Kidney Injury* ; Animals ; Apoptosis ; Bone Marrow ; Chimera ; Cytokines ; Fibrosis ; Inflammation ; Intercellular Adhesion Molecule-1 ; Kidney ; Mice ; Neutrophils* ; Phenotype ; Transendothelial and Transepithelial Migration ; Uromodulin

BACKGROUND/AIMS: Recent findings have demonstrated the occurrence of neutrophil transendothelial migration in the reverse direction (reverse TEM) and that endothelial junctional adhesion molecule C (JAM-C) is a negative regulator of reverse TEM. In this study, we tested the effects of a JAM-C blocking antibody on the resolution of kidney injuries and inflammation in a mouse model of cisplatin-induced acute kidney injury (AKI). METHODS: Cisplatin was administered via intraperitoneal injection. A JAM-C blocking antibody or a control immunoglobulin G was administered intraperitoneal at 1.5 mg/kg, with the injection being delayed until day 4 following cisplatin administration to restrict the effect of antibodies on recovery. RESULTS: After cisplatin injection, serum creatinine and histologic injuries peaked on day 4. Treatment with a JAM-C blocking antibody on days 4 and 5 promoted the functional and histologic recovery of cisplatin-induced AKI on days 5 and 6. Facilitating recovery with a JAM-C blocking antibody correlated with significantly increased circulating intercellular adhesion molecule 1+ Tamm-Horsfall protein+ neutrophils and significantly decreased renal neutrophil infiltration, indicating that facilitating reverse the TEM of neutrophils from the kidney to the peripheral circulation partially mediated the resolution of inflammation and recovery. CONCLUSIONS: These results demonstrated that reverse TEM is involved in the resolution of neutrophilic inflammation in cisplatin-induced AKI and that JAM-C is an important regulator of this process.
Acute Kidney Injury* ; Animals ; Antibodies ; Cisplatin ; Creatinine ; Immunoglobulin G ; Inflammation ; Injections, Intraperitoneal ; Junctional Adhesion Molecule C* ; Junctional Adhesion Molecules* ; Kidney ; Mice ; Neutrophil Infiltration ; Neutrophils ; Transendothelial and Transepithelial Migration

Naive CD4 T cells activated by antigen-presenting cells (APCs) undergo terminal differentiation in the periphery. Multiple mechanisms determine their fates, that is, whether they differentiate into conventional T (Tconv) cells or regulatory T (Treg) cells. The key event during Treg generation is expression of the transcription factor Foxp3, which is the lineage-determining regulator for Treg differentiation and function. Here we show that the transcription factor Batf3 acts as a fate-decision factor with respect to Tconv versus Tregs by restraining Treg differentiation. Batf3 was preferentially expressed in effector CD4 T cells but not in Treg cells, and ectopic expression of Batf3 inhibited Foxp3 induction. Batf3-deficient CD4 T cells favorably differentiated into Treg cells in vitro and in colonic lamina propria. Batf3 KO mice also showed enhanced Treg function in gut-associated immune disease models (for example, ovalbumin tolerance and inflammatory bowel disease models). Batf3 bound to the CNS1 region of the Foxp3 locus and reduced expression of the gene. Thus, Batf3 is a transcriptional suppressor of Treg differentiation.
Animals ; Antigen-Presenting Cells ; Colon ; Ectopic Gene Expression ; Immune System Diseases ; In Vitro Techniques ; Inflammatory Bowel Diseases ; Mice ; Mucous Membrane ; Ovalbumin ; T-Lymphocytes ; T-Lymphocytes, Regulatory* ; Transcription Factors*

Th17 cells promote inflammatory reactions, whereas regulatory T (Treg) cells inhibit them. Thus, the Th17/Treg cell balance is critically important in inflammatory diseases. However, the molecular mechanisms underlying this balance are unclear. Here, we demonstrate that casein kinase 2 (CK2) is a critical determinant of the Th17/Treg cell balance. Both the inhibition of CK2 with a specific pharmacological inhibitor, CX-4945, and its small hairpin RNA (shRNA)-mediated knockdown suppressed Th17 cell differentiation but reciprocally induced Treg cell differentiation in vitro. Moreover, CX-4945 ameliorated the symptoms of experimental autoimmune encephalomyelitis and reduced Th17 cell infiltration into the central nervous system. Mechanistically, CX-4945 inhibited the IL-6/STAT3 and Akt/mTOR signaling pathways. Thus, CK2 has a crucial role in regulating the Th17/Treg balance.
Casein Kinase II* ; Casein Kinases* ; Caseins* ; Central Nervous System ; Encephalomyelitis, Autoimmune, Experimental ; In Vitro Techniques ; RNA, Small Interfering ; T-Lymphocytes, Regulatory* ; Th17 Cells

PURPOSE: Escherichia coli sequence type (ST) 131, a multidrug-resistant clone causing extraintestinal infections, has rapidly become prevalent worldwide. However, the epidemiological and clinical features of pediatric infections are poorly understood. We aimed to explore the characteristics of ST131 Escherichia coli isolated from Korean children with urinary tract infections. METHODS: We examined 114 uropathogenic E. coli (UPEC) isolates from children hospitalized at Chung-Ang University Hospital between 2011 and 2014. Bacterial strains were classified into STs by partial sequencing of seven housekeeping genes (adk, fumC, gyrB, icd, mdh, purA, and recA). Clinical characteristics and antimicrobial susceptibility were compared between ST131 and non-ST131 UPEC isolates. RESULTS: Sixteen UPEC isolates (14.0%) were extended-spectrum β-lactamase (ESBL)-producers; 50.0% of ESBL-producers were ST131 isolates. Of all the isolates tested, 13.2% (15 of 114) were classified as ST131. There were no statistically significant associations between ST131 and age, sex, or clinical characteristics, including fever, white blood cell counts in urine and serum, C-reactive protein, radiologic abnormalities, and clinical outcome. However, ST131 isolates showed significantly lower rates of susceptibility to cefazolin (26.7%), cefotaxime (40.0%), cefepime (40.0%), and ciprofloxacin (53.3%) than non-ST131 isolates (65.7%, 91.9%, 92.9%, and 87.9%, respectively; P<0.001 for all). ESBL was more frequently produced in ST131 (53.3%) than in non-ST131 (8.1%) isolates (P<0.01). CONCLUSION: ST131 E. coli isolates were prevalent uropathogens in children at a single medical center in Korea between 2011 and 2014. Although ST131 isolates showed higher rates of antimicrobial resistance, clinical presentation and outcomes of patients were similar to those of patients infected with non-ST131 isolates.
C-Reactive Protein ; Cefazolin ; Cefotaxime ; Child* ; Ciprofloxacin ; Clone Cells ; Escherichia coli ; Fever ; Genes, Essential ; Humans ; Korea ; Leukocyte Count ; Multilocus Sequence Typing ; Urinary Tract Infections* ; Urinary Tract* ; Uropathogenic Escherichia coli*

No abstract available.
Female ; Humans ; Hyperaldosteronism* ; Spondylitis, Ankylosing*