Comparable humoral and cellular immunity against Omicron variant BA.4/5 of once-boosted BA.1/2 convalescents and twice-boosted COVID-19-naïve individuals.

The fourth vaccination dose confers additional protective immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with no prior coronavirus disease-19 (COVID-19). However, its immunological benefit against currently circulating BA.4/5 is unclear in individuals who have received a booster shot and been infected with Omicron variant BA.1/2. We analyzed immune responses in whom had been boosted once and did not have COVID-19 (n = 16), boosted once and had COVID-19 when BA.1/2 was dominant in Korea (Hybrid-6M group, n = 27), and boosted twice and did not have COVID-19 (Vx4 group, n = 15). Antibody binding activities against RBDo BA.1 and RBDo BA.4/5 , antigen-specific memory CD4+ and CD8+ T-cell responses against BA.4/5, and B-cell responses against SARS-CoV-2 wild-type did not differ statistically between the Hybrid-6M and Vx4 groups. The humoral and cellular immune responses of the Hybrid-6M group against BA.4/5 were comparable to those of the Vx4 group. Individuals who had been boosted and had an Omicron infection in early 2022 may not have high priority for an additional vaccination.

Kidney residency of VISTA-positive macrophages accelerates repair from ischemic injury.

Tissue-resident macrophages have unique tissue-specific functions in maintaining homeostasis and resolving inflammation. However, the repair role and relevant molecules of kidney-resident macrophages after ischemic injury remain unresolved. To this end, mice without kidney-resident R1 macrophages but containing infiltrating monocyte-derived R2 macrophages were generated using differential cellular kinetics following clodronate liposome treatment. When ischemia-reperfusion injury was induced in these mice, late phase repair was reduced. Transcriptomic and flow cytometric analyses identified that V-domain Ig suppressor of T cell activation (VISTA), an inhibitory immune checkpoint molecule, was constitutively expressed in kidney-resident R1 macrophages, but not in other tissue-resident macrophages. Here, VISTA functioned as a scavenger of apoptotic cells and served as a checkpoint to control kidney-infiltrating T cells upon T cell receptor-mediated stimulation. Together these functions improved the repair process after ischemia-reperfusion injury. CD14+ CD33+ mononuclear phagocytes of human kidney also expressed VISTA, which has similar functions to the mouse counterpart. Thus, VISTA is upregulated in kidney macrophages in a tissue-dependent manner and plays a repair role during ischemic injury.

Clinical significance of subclinical carotid atherosclerosis and its relationship with echocardiographic parameters in non-diabetic chronic kidney disease patients.

BACKGROUND: Non-diabetic chronic kidney disease (CKD) patients are a heterogeneous group with a variety of prognosis. We investigated the role of subclinical carotid atherosclerosis for the prediction of adverse cardiovascular (CV) outcomes in these patients, and tried to identify clinical and echocardiographic parameters associated with subclinical carotid atherosclerosis. METHODS: As a prospective design, 182 asymptomatic non-diabetic CKD patients underwent carotid ultrasonography and Doppler echocardiography. Carotid atherosclerosis was defined as a carotid intima-media thickness ≥1.0 mm and/or the presence of plaque. RESULTS: During the mean follow-up period of 28.8 ± 16.1 months, 23 adverse CV events occurred. Patients with carotid atherosclerosis (99, 54.4%) showed significantly higher rates of annual CV events than those without (8.6 vs. 1.5%, p <0.001). Particularly, the presence of carotid plaque was a powerful predictor of adverse CV outcomes (OR 7.80, 95% CI 1.45-45.97). Clinical parameters associated with the presence of subclinical carotid atherosclerosis were old age, previous history of hypertension, increased pulse pressure, and higher high-sensitivity C-reactive protein (hs-CRP) level. By echocardiography, early diastolic mitral annular velocity (E') and the ratio of early peak transmitral inflow velocity (E) to E' (E/E') were closely related with the presence of carotid atherosclerosis. A multivariate analysis showed that age, hs-CRP, and E/E' were significant determinants of carotid atherosclerosis. CONCLUSIONS: Carotid plaque, even subclinical, was closely associated with a poor prognosis in non-diabetic CKD patients. Increased age, hs-CRP level, and E/E' ratio may be useful markers suggesting the presence of carotid atherosclerosis in these patients.

Mass-produced gram-negative bacterial outer membrane vesicles activate cancer antigen-specific stem-like CD8+ T cells which enables an effective combination immunotherapy with anti-PD-1.

Despite the capability of extracellular vesicles (EVs) derived from Gram-negative and Gram-positive bacteria to induce potent anti-tumour responses, large-scale production of bacterial EVs remains as a hurdle for their development as novel cancer immunotherapeutic agents. Here, we developed manufacturing processes for mass production of Escherichia coli EVs, namely, outer membrane vesicles (OMVs). By combining metal precipitation and size-exclusion chromatography, we isolated 357 mg in total protein amount of E. coli OMVs, which was equivalent to 3.93 × 1015 particles (1.10 × 1010 particles/µg in total protein amounts of OMVs) from 160 L of the conditioned medium. We show that these mass-produced E. coli OMVs led to complete remission of two mouse syngeneic tumour models. Further analysis of tumour microenvironment in neoantigen-expressing tumour models revealed that E. coli OMV treatment causes increased infiltration and activation of CD8+ T cells, especially those of cancer antigen-specific CD8+ T cells with high expression of TCF-1 and PD-1. Furthermore, E. coli OMVs showed synergistic anti-tumour activity with anti-PD-1 antibody immunotherapy, inducing substantial tumour growth inhibition and infiltration of activated cancer antigen-specific stem-like CD8+ T cells into the tumour microenvironment. These data highlight the potent anti-tumour activities of mass-produced E. coli OMVs as a novel candidate for developing next-generation cancer immunotherapeutic agents.

Oncolytic Vaccinia Virus Augments T Cell Factor 1-Positive Stem-like CD8+ T Cells, Which Underlies the Efficacy of Anti-PD-1 Combination Immunotherapy.

Oncolytic virotherapy has garnered attention as an antigen-agnostic therapeutic cancer vaccine that induces cancer-specific T cell responses without additional antigen loading. As anticancer immune responses are compromised by a lack of antigenicity and chronic immunosuppressive microenvironments, an effective immuno-oncology modality that converts cold tumors into hot tumors is crucial. To evaluate the immune-activating characteristics of oncolytic vaccinia virus (VACV; JX-594, pexastimogene devacirepvec), diverse murine syngeneic cancer models with different tissue types and immune microenvironments were used. Intratumorally administered mJX-594, a murine variant of JX-594, potently increased CD8+ T cells, including antigen-specific cancer CD8+ T cells, and decreased immunosuppressive cells irrespective of tissue type or therapeutic efficacy. Remodeling of tumors into inflamed ones by mJX-594 led to a response to combined anti-PD-1 treatment, but not to mJX-594 or anti-PD-1 monotherapy. mJX-594 treatment increased T cell factor 1-positive stem-like T cells among cancer-specific CD8+ T cells, and anti-PD-1 combination treatment further increased proliferation of these cells, which was important for therapeutic efficacy. The presence of functional cancer-specific CD8+ T cells in the spleen and bone marrow for an extended period, which proliferated upon encountering cancer antigen-loaded splenic dendritic cells, further indicated that long-term durable anticancer immunity was elicited by oncolytic VACV.

Kidney VISTA prevents IFN-γ/IL-9 axis-mediated tubulointerstitial fibrosis after acute glomerular injury.

Severe glomerular injury ultimately leads to tubulointerstitial fibrosis that determines patient outcome, but the immunological molecules connecting these processes remain undetermined. The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, plays a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. After acute glomerular injury using nephrotoxic serum, tubules in the VISTA-deficient (Vsir-/-) kidney suffered more damage than those in WT kidneys. When interstitial immune cells were examined, the contact frequency of macrophages with infiltrated T cells increased and the immunometabolic features of T cells changed to showing high oxidative phosphorylation and fatty acid metabolism and overproduction of IFN-γ. The Vsir-/- parenchymal tissue cells responded to this altered milieu of interstitial immune cells as more IL-9 was produced, which augmented tubulointerstitial fibrosis. Blocking antibodies against IFN-γ and IL-9 protected the above pathological process in VISTA-depleted conditions. In human samples with acute glomerular injury (e.g., antineutrophil cytoplasmic autoantibody vasculitis), high VISTA expression in tubulointerstitial immune cells was associated with low tubulointerstitial fibrosis and good prognosis. Therefore, VISTA is a sentinel protein expressed in kidney macrophages that prevents tubulointerstitial fibrosis via the IFN-γ/IL-9 axis after acute antibody-mediated glomerular injury.

Hepatitis B virus reactivation in a primary central nervous system lymphoma patient following intrathecal rituximab treatment.

A 69-year-old woman with relapsed primary central nervous system (CNS) lymphoma was treated with intrathecal rituximab without a concomitant systemic steroid or other chemotherapeutic drugs. Her initial viral status was HBs Ag negative and anti-HBs Ab positive. After 12 weeks of the last intrathecal rituximab application, the levels of AST and ALT were 1,005 and 1,134 IU/l, respectively. The viral status was changed as follows: HBs Ag positive, anti-HBs Ab negative, anti-HBe Ag positive, and anti-HBe Ab negative. The titer of hepatitis B virus (HBV) DNA was 106,000 IU/ml. She was diagnosed with acute hepatitis due to HBV reactivation. To our knowledge, this is the first reported case of HBV reactivation occurring after intrathecal rituximab monotherapy, suggesting that monitoring of HBV markers should be considered during intrathecal rituximab treatment in primary CNS lymphoma patients who are HBs Ag positive or anti-HBs Ab positive.

Immune cell composition in normal human kidneys.

An understanding of immunological mechanisms in kidney diseases has advanced using mouse kidneys. However, the profiling of immune cell subsets in human kidneys remains undetermined, particularly compared with mouse kidneys. Normal human kidneys were obtained from radically nephrectomised patients with urogenital malignancy (n = 15). Subsequently, human kidney immune cell subsets were analysed using multicolor flow cytometry and compared with subsets from C57BL/6 or BALB/c mice under specific pathogen-free conditions. Twenty kidney sections from healthy kidney donors or subjects without specific renal lesions were additionally analysed by immunohistochemistry. In human kidneys, 47% ± 12% (maximum 63%) of immune cells were CD3+ T cells. Kidney CD4+ and CD8+ T cells comprised 44% and 56% of total T cells. Of these, 47% ± 15% of T cells displayed an effector memory phenotype (CCR7- CD45RA- CD69-), and 48% ± 19% were kidney-resident cells (CCR7- CD45RA- CD69+). However, the proportions of human CD14+ and CD16+ myeloid cells were approximately 10% of total immune cells. A predominance of CD3+ T cells and a low proportion of CD14+ or CD68+ myeloid cells were also identified in healthy human kidney sections. In mouse kidneys, kidney-resident macrophages (CD11blow F4/80high) were the most predominant subset (up to 50%) but the proportion of CD3+ T cells was less than 20%. These results will be of use in studies in which mouse results are translated into human cases under homeostatic conditions or with disease.

Blue toe syndrome treated with sympathectomy in a patient with acute renal failure caused by cholesterol embolization.

Blue toe syndrome is the most frequent manifestation of tissue ischemia caused by cholesterol embolization (CE), which can lead to amputation of affected lower extremities, if severe. However, any effective treatment is lacking. We experienced a case of spontaneously presenting blue toe syndrome and concomitant acute renal failure in a patient with multiple atherosclerotic risk factors. CE was confirmed by renal biopsy. Despite medical treatment including prostaglandin therapy and narcotics, the toe lesion progressed to gangrene with worsening ischemic pain. Therefore, we performed lumbar sympathectomy, which provided dramatic pain relief as well as an adequate blood flow to the ischemic lower extremities, resulting in healing of the gangrenous lesion and avoiding toe amputation. This is the first reported case of a patient with intractable ischemic toe syndrome caused by CE that was treated successfully by sympathectomy. Our observations suggest that sympathectomy may be beneficial in some patients with CE-associated blue toe syndrome.

Left ventricular diastolic dysfunction as a predictor of rapid decline of residual renal function in patients with peritoneal dialysis.

BACKGROUND: The aim of this study was to evaluate whether diastolic dysfunction at the start of dialysis could influence renal and cardiovascular survival rates in 82 patients undergoing peritoneal dialysis. METHODS: Diastolic dysfunction was determined using left ventricular hypertrophy, the ratio of early peak transmitral inflow velocity to peak diastolic mitral annular velocity (E/E'), and left atrial volume index (LAVI). Residual renal function (RRF) was measured with 24-hour urine collections at baseline (within 1 month of beginning peritoneal dialysis) and thereafter at 6-month intervals for 2 years. To evaluate the long-term prognostic significance of diastolic dysfunction, the 4-year cardiac event-free survival was also evaluated. RESULTS: The median slope of RRF decline was -0.07 mL/min/mo/1.73 m(2). Forty-five patients (54.9%) with rapid RRF declines (< -0.07 mL/min/mo/1.73 m(2)) had a higher prevalence of diabetes and eccentric left ventricular hypertrophy, as well as significantly elevated E/E' ratios and LAVIs. There was a close relationship between baseline E/E' ratio (r = -0.221, P = .048), LAVI (r = -0.276, P = .015), and RRF decline rate, and both E/E' > 15 (odds ratio, 3.61; 95% confidence interval, 1.07-12.12) and LAVI > 32 mL/m(2) (odds ratio, 3.54; 95% confidence interval, 1.08-11.58) were significant independent predictors of the loss of RRF. Furthermore, E/E' > 15 also provided additional prognostic value in predicting future cardiac events (hazard ratio, 6.74; 95% confidence interval, 1.07-12.12; P = .023). CONCLUSIONS: Left ventricular diastolic dysfunction may be a significant predictor of rapid decline in RRF and adverse cardiac outcomes in patients starting peritoneal dialysis.

Austrian syndrome with a delayed onset of heart failure.

A 59-year-old man treated with pneumococcal meningitis 4 months ago was hospitalized for acute heart failure and performed aortic valve replacement by rupture of aortic valve. The frequent association of pneumococcal meningitis and endocarditis is known as Austrian syndrome. Though Austrian syndrome is a clinically rare disease, the evolution of pneumococcal endocarditis is very aggressive and associated with high mortality, and early recognition for evidence of endocardial lesion in patients with pneumococcal meningitis is important to reduce the complications and mortality rate.