Association of baseline histopathology and kidney donor risk index with graft outcomes in deceased donor kidney transplantation
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BACKGROUND: Donor organ quality is a key determinant of graft outcomes in deceased donor kidney transplantation (DDKT). The predictive values of baseline histopathology and several clinical scoring systems for long-term graft outcomes have been evaluated, but the results remain controversial. MATERIALS AND METHODS: We screened 167 patients who underwent DDKT at Ulsan University Hospital from April 2003 to June 2016. Among them, 66 patients who underwent baseline kidney biopsy and whose kidney donor risk index (KDRI) was available were included in this analysis. All baseline biopsies were rescored according to the updated Banff classification. RESULTS: Median follow-up was 22 months. Mean age of recipients and donors was 51.4 and 44.7 years, respectively. Mean KDRI was 1.40 ± 0.44. During follow-up, delayed graft function and biopsy-proven acute rejection (BPAR) developed in 7 and 11 patients, respectively. Graft failure occurred in 2 patients. In Cox regression analysis, interstitial fibrosis/tubular atrophy (IFTA) (hazard ratio (HR) = 3.59; p = 0.049) was a significant risk factor for BPAR. In multivariate linear regression, age (standardized ß (SB) = -0.282; p = 0.002), BPAR (SB = -0.406; p < 0.001), KDRI (SB = -0.277; p = 0.003), and IFTA (SB = -0.298; p = 0.001) were significant predictors of last-visit estimated glomerular filtration rate (eGFR). CONCLUSION: Several clinical and pathologic parameters, such as KDRI and IFTA, may be helpful for predicting long-term graft outcomes, including BPAR and last-visit eGFR, in DDKT.
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Outcomes of Spontaneous Isolated Superior Mesenteric Artery Dissection Without Antithrombotic Use.

OBJECTIVES: This study aimed to show the intention to treat results of treatment for spontaneous isolated superior mesenteric artery dissection (SISMAD) without anticoagulation or antiplatelet agents and the follow-up results of SISMAD according to the configuration on computed tomography (CT) scans. DESIGN: Retrospective, observational single centre study METHODS: All cases of SISMAD were enrolled consecutively from 2006 onwards. There were 25 symptomatic and four asymptomatic patients in whom SISMAD was found incidentally. The SISMAD patients were treated using a consistent therapeutic strategy without antithrombotics. SISMAD was categorized into four types based on the configuration on CT scans by Yun's classification. Follow-up CT was performed at 3 months, 6 months, and yearly thereafter. RESULTS: The median follow-up duration was 57 months (13-129 months). Improvement or complete resolution on CT scans, with no symptom recurrence, was seen in 27 patients. The non-invasive approach failed in three cases and two patients underwent further intervention. No patient died during the follow-up. CONCLUSIONS: Weighing the risks versus benefits of antithrombotics and considering the benign nature of SISMAD, conservative treatment without antithrombotics might be sufficient in patients without evidence of bowel ischaemia or infarction on initial CT scan.

Meiotic prophase roles of Rec8 in crossover recombination and chromosome structure.

Rec8 is a prominent component of the meiotic prophase chromosome axis that mediates sister chromatid cohesion, homologous recombination and chromosome synapsis. Here, we explore the prophase roles of Rec8. (i) During the meiotic divisions, Rec8 phosphorylation mediates its separase-mediated cleavage. We show here that such cleavage plays no detectable role for chromosomal events of prophase. (ii) We have analyzed in detail three rec8 phospho-mutants, with 6, 24 or 29 alanine substitutions. A distinct 'separation of function' phenotype is revealed. In the mutants, axis formation and recombination initiation are normal, as is non-crossover recombination; in contrast, crossover (CO)-related events are defective. Moreover, the severities of these defects increase coordinately with the number of substitution mutations, consistent with the possibility that global phosphorylation of Rec8 is important for these effects. (iii) We have analyzed the roles of three kinases that phosphorylate Rec8 during prophase. Timed inhibition of Dbf4-dependent Cdc7 kinase confers defects concordant with rec8 phospho-mutant phenotypes. Inhibition of Hrr25 or Cdc5/polo-like kinase does not. Our results suggest that Rec8's prophase function, independently of cohesin cleavage, contributes to CO-specific events in conjunction with the maintenance of homolog bias at the leptotene/zygotene transition of meiotic prophase.

De novo low-dose sirolimus versus mycophenolate mofetil in combination with extended-release tacrolimus in kidney transplant recipients: a multicentre, open-label, randomized, controlled, non-inferiority trial.

BACKGROUND: Most of the previous studies reported that tacrolimus (TAC) with sirolimus (SRL) was associated with worse post-transplant outcomes in kidney transplantation, compared with TAC with mycophenolate mofetil (MMF). These might be attributable to high-dose SRL. However, outcomes using low-dose SRL with TAC for kidney transplantation are uncertain. The aim of this study was to assess the efficacy and safety of low-dose SRL with extended-release tacrolimus (ER-TAC) versus MMF with ER-TAC. METHODS: We randomly assigned 158 renal transplant patients to receive low-dose SRL or MMF in combination with ER-TAC and corticosteroid. The primary endpoint was the composite efficacy failure rate, including biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up, within 12 months post-transplantation. This trial is registered with ClinicalTrial.gov (number NCT01680952). RESULTS: The efficacy failure rate was 6.6% in the low-dose SRL group and 13.3% in the MMF group in the intention-to-treat population (absolute difference, 6.8%; 95% confidence interval, -2.8% to 16.3%). The incidence of BPAR within 12 months post-transplantation was 5.3% in the low-dose SRL group and 13.3% in the MMF group (P = 0.09). The mean estimated glomerular filtration rate at 12 months post-transplantation was 53.2 mL/min/1.73 m2 in the low-dose SRL group and 52.4 mL/min/1.73 m2 in the MMF group (P = 0.76). The incidences of adverse events and serious adverse events were similar between groups. CONCLUSION: Low-dose SRL with ER-TAC was not inferior to MMF with ER-TAC with respect to efficacy and safety. When used for immunosuppression in kidney transplantation, low-dose SRL with ER-TAC can effectively prevent acute rejection and preserve renal function.

Low-dose mycophenolate mofetil in tablet form or capsule form combined with tacrolimus in the early period after kidney transplantation: a prospective randomized trial
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AIMS: The tablet form (500 mg) of mycophenolate mofetil (MMF) provides more convenience of taking drugs and cost-effectiveness than the capsule form (250 mg). We examined the efficacy and safety of MMF in its different forms combined with tacrolimus in kidney transplant recipients. METHODS: This multicenter, 26-week, randomized trial was performed to compare the efficacy and safety of the tablet form of MMF versus the capsule form of MMF in 156 kidney transplant recipients. Allograft function, the incidence of efficacy failure (biopsy-proven acute rejection (BPAR), death, graft loss, or loss to follow-up), and adverse events were compared. RESULTS: The mean dose (mg/day) of MMF at 26 weeks was comparable: 1,052.6 ± 194.2 in the tablet group vs. 1,155.6 ± 298.1 in the capsule group (p = 0.063). Trough levels of tacrolimus at 26 weeks were comparable. The mean estimated glomerular filtration rate of the tablet group at 26 weeks post-transplant was not inferior to that of the capsule group. The incidence of efficacy failure was similar in the two groups: tablet group, 5.2% and capsule group, 7.7% (difference -2.5%; 95% confidence interval -5.22 - 10.21%). The incidence of BPAR until 26 weeks post-transplant in the tablet group was 3.9%, compared to 7.7% in the capsule group (p = 0.346). There was no significant difference in the incidence of discontinuations and serious adverse events between the groups. CONCLUSION: Low-dose MMF in tablet form combined with tacrolimus can be considered as an efficacious and safe immunosuppressive regimen in the early period after kidney transplantation.
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A nationwide study of regional preference and graft survival of kidney transplantation in South Korea: patterns of centralization in the capital area.

Purpose: This study aims to investigate regional patterns and graft survival rates in kidney transplantation (KT) within South Korea using the National Health Insurance Service database. Methods: By analyzing KT data from 2002 to 2017, including patient residency, KT location, and post-KT dialysis information, graft survival was assessed through post-KT dialysis and validated against Ulsan University Hospital and the Korean Organ Transplantation Registry's 2017 report. Results: Among the 20,978 KTs, 60.5% occurred in the Korean capital, Seoul, whereas 39.5% occurred outside. The overall graft survival rate was 81.5% with a median survival duration of 57 months. Patient survival was 83.8%, with a median survival duration of 61 months. For KTs from 2002 to 2007, the 10-year graft and patient survival rates were 89.1% and 90.3%, respectively. The KT recipients living outside Seoul who underwent the KT within their residential regions had a graft survival rate of 88.3%, and those receiving KTs outside their original region had a graft survival rate of 88.0%. Among Seoul residents who underwent KTs in the city, the graft survival rate was 90.5%. Importantly, hospital location did not significantly affect graft survival rates (P = 0.136). Conclusion: This study revealed a regional preference for KT in South Korea, particularly in the capital city, likely because of nonresidents. Nevertheless, the graft and patient survival rates showed no significant regional disparities. These findings emphasize the necessity for equitable KT service access across regions in order to optimize patient outcomes.

Efficacy and Safety of Early Anti-inflammatory Drug Therapy for Secondary Injury in Traumatic Brain Injury.

BACKGROUND: Brain injury following head trauma occurs in 2 stages, namely an early stage attributable to mechanical damage and a delayed stage resulting primarily from neuroinflammation. In this study, we examined early proinflammatory cytokine upregulation in an animal model of traumatic brain injury (TBI) and examined the effects of early anti-inflammatory therapy on neuroinflammation, neuropathology, and systemic inflammatory activity. METHODS: Seven-week-old C57BL/6 mice (20 g-25 g) were subjected to sham treatment or closed skull impact from a 30-g round weight dropped 15 cm onto the cortical midpoint. Model mice were then randomly assigned to receive intraperitoneal phosphate-buffered saline (control), 20 mg/kg cyclosporine A, 2 mg/kg dexamethasone, or 5 mg/kg cholecalciferol 1 hour post-TBI. Body weight, brain weight, cytokine expression in the brain and draining lymph nodes (DLNs), and histopathological changes were measured at multiple times post-TBI. RESULTS: Body weight did not significantly differ among the groups, whereas the brain-to-body weight ratio was significantly lower in the control group 7 days post-TBI. The peak expression of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 in the brain and DLNs 6 hours post-TBI was significantly lower in the dexamethasone and cyclosporine A groups. Conversely, peak IL-10 expression in the brain and DLNs was elevated in the cholecalciferol group. Control mice exhibited earlier and more severe neuroinflammatory damage than those in the experimental groups. CONCLUSIONS: The administration of anti-inflammatory drugs or vitamin D analogs in the early period following TBI might help to reduce secondary injury from neuroinflammation.

Outgrowing skin involvement in malakoplakia after kidney transplantation: A case report.

INTRODUCTION: Malakoplakia is a rare pseudotumor that arises in the context of recurrent infections, particularly in immunocompromised states. We report a case of renal allograft parenchymal malakoplakia. CASE REPORT: A 59-year-old woman successfully received a cadaveric renal transplant in June 2018. Two months after transplantation, she was treated for a urinary tract infection (UTI). In March 2019, she underwent allograft biopsy for increasing creatinine. The biopsy identified T cell mediated rejection and steroid pulse therapy was performed. In December 2019, she was hospitalized for right flank pain and pyuria, and her creatinine level was 1.9 mg/dL. Radiographic findings were suggestive of a hematoma or abscess in the perirenal area, and septated fluid collection was suspected. Biopsy results suggested malakoplakia, and von Kossa stain was positive for Michaelis- Gutmann bodies. Tissue culture demonstrated Escherichia coli, and this was treated with antibiotics. The dose of tacrolimus was reduced. The patient was discharged after 1 month of hospitalization and was maintained on oral antibiotics. Follow-up imaging revealed an increase in the extent of lesion into the adjacent abdominal wall. Assuming the case to be refractory, we performed surgical resection and abscess drainage. Although the renal parenchymal involvement persisted, the size showed a decreasing trend over 2 months of serial observation with ultrasonography. CONCLUSIONS: Malakoplakia should be considered as a differential diagnosis for recurrent UTI with graft dysfunction. Malakoplakia can be successfully treated with reduction in immunosuppression and medical therapy using long-term antibiotic treatment in most cases. However, early surgical treatment must be considered for refractory cases.

Potential involvement of CCL23 in atherosclerotic lesion formation/progression by the enhancement of chemotaxis, adhesion molecule expression, and MMP-2 release from monocytes.

OBJECTIVE: CCL23 [Ckß8-1/myeloid progenitor inhibitory factor 1 (MPIF1)/macrophage inflammatory protein-3 (MIP3)], a member of the CC chemokine family, is involved in leukocyte trafficking, and implicated in inflammatory diseases. In the present study, we investigated the role of CCL23 in the development of human atherosclerosis, which is characterized by an inflammatory disease. METHODS: CCL23 transcripts were measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and CCL23 protein by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). Expression of adhesion molecules was determined by flow cytometry, and matrix metalloproteinase-2 (MMP-2) levels by zymography. RESULTS: Proatherogenic factors such as oxidized low-density lipoprotein (oxLDL) and oxidative stress markedly enhanced CCL23 release from human THP-1 macrophages. CCL23 stimulated chemotaxis of human THP-1 monocytes in a dose-dependent manner and enhanced the expression of adhesion molecule CD11c, as well as release of MMP-2 from the THP-1 monocytes. Moreover, CCL23 expression at the mRNA level was significantly higher in human atherosclerotic lesions than in normal arteries, and CCL23 protein was co-expressed with CD68, a specific marker for macrophages. Circulating levels of plasma CCL23 were higher in atherosclerotic patients than in normal subjects. CONCLUSION: These findings suggest that CCL23 plays a role in the development of human atherosclerosis. CCL23 may be a useful target for the development of antiatherogenic agents.

Risk Due to ABO Incompatibility and Donor-Recipient Weight Mismatch in Living Donor Kidney Transplantation: A National Cohort Study.

The effect of donor-recipient weight mismatch is not well established in ABO-incompatible living donor kidney transplantation (LDKT). A total of 2584 LDKT patients in the Korean Organ Transplantation Registry were classified into four groups according to the presence or absence of ABO incompatibility and donor-recipient weight mismatch (donor-to-recipient weight ratio (DRWR) < 0.8). In a multivariable Cox analysis, the combination of ABO incompatibility and DRWR incompatibility (n = 124) was an independent risk factor for graft survival (HR = 2.73, 95% CI = 1.11-6.70) and patient survival (HR = 3.55, 95% CI = 1.39-9.04), whereas neither factor alone was a significant risk factor for either outcome. The combination of ABO incompatibility and DRWR incompatibility was not an independent risk factor for biopsy-proven graft rejection (HR = 1.27, 95% CI = 0.88-1.82); however, it was an independent risk factor for pneumonia (HR = 2.94, 95% CI = 1.64-5.57). The mortality rate due to infection was higher among patients with both ABO incompatibility and DRWR incompatibility than among patients with neither factor or with either factor alone. The combination of ABO incompatibility and DRWR incompatibility was an independent risk factor for graft and patient survival after LDKT, whereas neither factor alone significantly affected graft or patient survival. Thus, donor-recipient weight matching should be cautiously considered in LDKT with ABO incompatibility.

Improvement of medication adherence with simplified once-daily immunosuppressive regimen in stable kidney transplant recipients: A prospective cohort study.

BACKGROUND: Many immunosuppressive drugs are prescribed as twice-daily dosing. A simplified once-daily dosing of immunosuppressive drug regimen may improve medication adherence. We investigated medication adherence of simplified once-daily immunosuppressive regimen consisting of extended-release tacrolimus, sirolimus, and corticosteroids along with the efficacy and safety of this regimen. METHODS: This study was a prospective, multicenter, controlled and cohort trial. Stable kidney transplant recipients who had received transplantation at least 3 months before the study enrollment were eligible for the study. Participants were required to fill-out the self-reported immunosuppressant therapy barrier scale (ITBS) questionnaire before and after the conversion. Other clinical laboratory parameters and adverse events were evaluated until 6 months post-conversion. RESULTS: A total of 160 kidney recipients comprised the intention-to-treat population. The mean total ITBS score was 19.5 ± 4.0 at pre-conversion and 6 months after converting, the mean total ITBS score was 16.6 ± 3.6 (p < 0.001). Particularly, the ITBS scores of 4 questions related to the frequency of medication dosing were significantly different between pre-conversion and post-conversion. Only 1 patient (0.62%) was diagnosed as biopsy-confirmed acute rejection in the study period. There was no significant change in the mean estimated glomerular filtration rate after the conversion. Overall 95 patients (59.4%) had an adverse event and 28 patients (17.5%) had a serious adverse event. No graft loss and 1 death were reported. CONCLUSION: Medication adherence after the conversion to the once-daily immunosuppressive regimen was significantly improved with no additional risks of efficacy failure or adverse events.

CD137 Signaling Regulates Acute Colitis via RALDH2-Expressing CD11b-CD103+ DCs.

CD137, a potent costimulatory receptor for CD8+ T cells, is expressed in various non-T cells, but little is known about its regulatory functions in these cells. In this study, we show that CD137 signaling, specifically in intestinal CD11b-CD103+ dendritic cells (DCs), restricts acute colitis progression. Mechanistically, CD137 engagement activates TAK1 and subsequently stimulates the AMPK-PGC-1α axis to enhance expression of the Aldh1a2 gene encoding the retinoic acid (RA) metabolizing enzyme RALDH2. RA can act on CD11b+CD103- DCs and induce SOCS3 expression, which, in turn, suppresses p38MAPK activation and interleukin-23 (IL-23) production. Administration of RA in DC-specific CD137-/- mice represses IL-23-producing CD11b+CD103- DCs and TH17 cells, indicating that RA is a major inhibitory effector molecule against intestinal CD11b+CD103- DCs. Additionally, the therapeutic effect of the anti-CD137 antibody is abrogated in DC-specific CD137-/- mice. Taken together, our results define a mechanism of paracrine immunoregulation operating between adjacent DC subsets in the intestine.

Stimulation of the molecule 4-1BB enhances host defense against Listeria monocytogenes infection in mice by inducing rapid infiltration and activation of neutrophils and monocytes.

The tumor necrosis factor receptor family molecule 4-1BB (CD137) has diverse roles in adaptive and innate immune responses. However, little is known of its role in bacterial infections. Previously, we showed that 4-1BB-deficient mice have enhanced susceptibility to Listeria monocytogenes infection, and mice pretreated with agonistic anti-4-1BB antibody (3E1) were much more resistant to L. monocytogenes infection than mice treated with control antibody. In this study, we report that stimulating 4-1BB by administering 3E1 in the early phase of L. monocytogenes infection is critical for promoting the survival of mice by inducing rapid infiltration of neutrophils and monocytes into L. monocytogenes-infected livers. The levels of tumor necrosis factor alpha, interleukin 6, and monocyte chemoattractant protein 1 in the livers of 3E1-treated mice increased as early as 30 min postinfection and peaked by 1 to 2 h, while those in mice treated with control antibody started to increase only at 16 h postinfection. Monocytes and neutrophils from the 3E1-treated mice had higher levels of activation markers, phagocytic activity, and reactive oxygen species than those from control mice. In vitro stimulation of 4-1BB induced the production of the inflammatory cytokines/chemokines of neutrophils, but not those of monocytes. These results suggest that 4-1BB stimulation of neutrophils in the early phase of L. monocytogenes infection causes rapid production of inflammatory cytokines/chemokines and that the subsequent infiltration of neutrophils and monocytes is crucial for eliminating the infecting L. monocytogenes.

Kidney Donation From a Patient Who Underwent Endovascular Aneurysm Repair.

Organ shortage is the greatest challenge facing the field of organ transplantation in Korea. There are no reports of patients who have undergone endovascular aneurysm repair being considered as kidney donors. We successfully performed kidney transplant procedures in a 62-year-old man and a 57-year-old man using kidneys recovered from a 67-year-old female brain-dead donor who underwent endovascular aneurysm repair 6 months before organ retrieval. To the best of our knowledge, this is the first report of transplants performed with organs from a donor who previously underwent endovascular aneurysm repair.

Factors of Acute Kidney Injury Donors Affecting Outcomes of Kidney Transplantation From Deceased Donors.

BACKGROUND: This study aimed to investigate the outcomes of kidney transplantation (KT) from deceased acute kidney injury (AKI) donors and analyzed the factors affecting these outcomes. METHODS: All patients who underwent KT from deceased donors at our institution from 1998 to 2016 were retrospectively reviewed. Recipients were divided into the AKI and non-AKI donor groups. We analyzed delayed graft function (DGF), serum creatinine levels at 1 month and 1 year after KT, cold ischemia time, donors' initial and terminal serum creatinine levels, Kidney Donor Profile Index, and patient and graft survival in each group. RESULTS: Of 181 recipients, 30 received kidneys from 21 AKI donors, whereas the remaining 151 received kidneys from donors without AKI. DGF more frequently developed in the AKI donor group than in the non-AKI donor group (40% vs 7.28%; P = .001). Allograft functions at 1 month and 1 year after KT did not differ between the AKI and non-AKI donor groups (1 month: P = .469; 1 year: P = .691). Factors affecting DGF were recipient weight and donor AKI. Recipient factors affecting graft function at 1 year were recipient height, length of hospital stay, serum creatinine levels at 1 month and 6 months, and biopsy-proven acute rejection. Older donor age was the only donor factor that affected graft function at 1 year. CONCLUSION: KT from deceased AKI donors showed a higher DGF rate but favorable patient and graft survival and graft functions. Donor AKI and recipient weight affected DGF, and only older donor age affected graft function at 1 year.

Reactive oxygen species-dependent EndoG release mediates cisplatin-induced caspase-independent apoptosis in human head and neck squamous carcinoma cells.

Cisplatin is a chemotherapeutic agent that is widely used to treat cancers such as head and neck squamous cell carcinoma (HNSCC). Previously, we have reported that cisplatin induced an early caspase-dependent apoptosis (8 hr) in a HNSCC cell, HN4. In this study, we examined a late caspase-independent apoptosis as well as an early caspase-dependent apoptosis in cisplatin-treated HN4 cells. While z-VAD-fmk, a pan-caspase inhibitor, blocked the caspase activities and protected cells from the early apoptosis, it did not provide protection against delayed apoptosis occurring after extended exposure (16 hr) to cisplatin, suggesting that the delayed apoptotic response in the presence of z-VAD-fmk was caspase-independent. Cisplatin treatment induced reactive oxygen species (ROS) generation, loss of the mitochondrial membrane potential (MMP) and nuclear translocation of endonuclease G (EndoG). Small interfering RNA mediated-knockdown of EndoG significantly protected cells from the delayed apoptosis induced by cisplatin in the presence of z-VAD-fmk. Overexpression of Bcl-2 in HN4 cells prevented loss of MMP, nuclear translocation of EndoG and protected cells from the delayed apoptosis induced by cisplatin in the presence of z-VAD-fmk. Pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger, prevented both ROS generation, loss of the MMP and nuclear translocation of EndoG. Together, our data indicate that cisplatin treatment induced ROS-mediated loss of the MMP, and, then, the nuclear translocation of EndoG, which played a crucial role in caspase-independent apoptosis of HN4 cells in the presence of z-VAD-fmk. This is the first report about the involvement of EndoG in cisplatin-induced caspase-independent apoptosis of cells.

NF-kappaB activation is required for cisplatin-induced apoptosis in head and neck squamous carcinoma cells.

This study demonstrates a requirement for NF-kappaB activation in cis-diamminedichloroplatinum (cisplatin)-induced apoptosis in human head and neck squamous cell carcinoma (HNSCC) cell lines. This conclusion was supported by the following observations: cisplatin induced IkappaBalpha degradation and NF-kappaB-dependent transcriptional activation prior to cell death; pyrrolidine dithiocarbamate (PDTC), a chemical inhibitor of NF-kappaB activation, prevented apoptosis; lactacystin, an inhibitor of IkappaBalpha degradation, also prevented apoptosis; and finally, the expression of a super-repressor mutant IkappaBalpha blocked apoptosis. The expression of tumor necrosis factor alpha (TNFalpha) was promoted by cisplatin treatment and was suppressed by PDTC treatment. In addition, a neutralizing antibody against TNFalpha protected cells from cisplatin-induced apoptosis. These findings suggest that NF-kappaB activation is required for cisplatin-induced apoptosis and TNFalpha may play an important role in NF-kappaB-mediated apoptosis in cisplatin-treated HNSCC cell lines.

4-1BB (CD137) signals depend upon CD28 signals in alloimmune responses.

Our previous study has demonstrated that there is a significant delay of Balb/c cardiac allograft rejection in the C57BL/6 4-1BB-deficient knockout recipient. In this study, we examined the effect of combined blockade of the 4-1BB and CD28 costimulatory pathways on cardiac allograft rejection in the C57BL/6-->Balb/c model. A long-term cardiac allograft survival was induced in CD28/4-1BB- deficient mice (>100 days survival in 3 of 4 mice), which was comparable with CD28-deficient mice (>100 days survival in 2 of 5 mice; P<0.2026). There was no long-term cardiac allograft survival in either wild-type (WT) or 4-1BB-deficient mice, even though 4-1BB-deficient recipients showed a significant delay of cardiac allograft rejection than WT mice. An in vitro mixed leukocyte reaction (MLR) assay showed that 4-1BB-deficient and WT mouse T cells had a similar responsiveness to allostimulation, whereas CD28- and CD28/4-1BB-deficient mouse T cells had a defective responsiveness to allostimulation. Furthermore, 4-1BB-deficient mice showed a similar CTL but an elevated Ab response against alloantigens as compared to WT mice, and the alloimmune responses of 4-1BB-deficient mice were abrogated in the CD28-deficient background. Overall, these results indicate that the CD28 costimulatory pathway plays a major role in the alloimmune response and that 4-1BB signals are dependent upon CD28 signals.

Roles of IL-33 in Resistance and Tolerance to Systemic Candida albicans Infections.

IL-33 is a multifunctional cytokine that is released in response to a variety of intrinsic and extrinsic stimuli. The role of IL-33 in Candida albicans infections is just beginning to be revealed. This cytokine has beneficial effects on host defense against systemic C. albicans infections, and it promotes resistance mechanisms by which the immune system eliminates the invading fungal pathogens; and it also elevates host tolerance by reducing the inflammatory response and thereby, potentially, tissue damage. Thus, IL-33 is classified as a cytokine that has evolved functionally to protect the host from damage by pathogens and immunopathology.