Provision of antifungal immunity and concomitant alloantigen tolerization by conditioned dendritic cells in experimental hematopoietic transplantation

FoxP3(+) regulatory T (Treg) cells are important mediators of peripheral tolerance, and deficiency of this population is associated with autoimmune inflammation and onset of acute lethal graft-vs.-host disease in transplantation. Type I IFN-producing plasmacytoid dendritic cells (pDC) are implicated in the induction and maintenance of tolerance and contribute to engraftment facilitation and prevention of graft-vs.-host disease after allogeneic hematopoietic stem cells transplantation (HSCT). Because host DC function is impaired during the immediate period post-transplant, the administration of donor DC may be useful for the educational program of recovering T cells. Distinct DC subsets could be derived from bone marrow (murine) or peripheral CD14(+) cell (human) cultures in the presence of either GM-CSF/IL-4 (myeloid DC) or FLT3-ligand (mainly pDC). The ability of either DC subset to induce Th1/Treg cell priming against Aspergillus fumigatus as well as the relative contribution of murine DC subsets to antifungal priming upon adoptive transfer in hematopoietic transplanted mice with aspergillosis is not known. We found specialization and complementarity in priming and tolerization by the different DC subsets, with FL-DC fulfilling the requirement for (i) Th1/Treg antifungal priming; ii) tolerization toward alloantigens and (iii) diversion from alloantigen-specific to antigen-specific T cell responses in the presence of donor T lymphocytes. Interestingly, thymosin alpha1 (Talpha1), known to modulate human pDC functions trough TLR9, affects mobilization and tolerization of pDC by activating the indoleamine 2,3-dioxygenase-dependent pathway, and this resulted in Treg development and tolerization. Thus, transplantation tolerance and concomitant pathogen clearance could be achieved through the therapeutic induction of antigen-specific Treg cells via instructive immunotherapy with pathogen- or TLR-conditioned donor DC.     

Altered microperfusion at the rectal stump is predictive for rectal anastomotic leak

PURPOSE: The aim of this study was to evaluate the reliability of intraoperative laser-Doppler measurements in predicting the occurrence of anastomotic leak in patients with colorectal cancer undergoing stapled straight anastomosis to the rectum. METHODS: A prospective study was undertaken on 55 patients with rectal cancer or distal sigmoid cancer programmed for elective curative surgery. In all patients transmural colonic blood flow was measured by laser-Doppler flowmetry technique before bowel manipulation (baseline measurement) and after vascular ligation and division. Comorbidities at admission, intraoperative events, associated surgical procedures, and clinical outcome were tested for any association with anastomotic leak. RESULTS: Postoperative mortality was 1.8 percent (1/55 patients), and the overall morbidity was 21.3 percent. Anastomotic leak occurred in eight patients (14.5 percent). After colonic division a blood flow reduction at the rectal stump was observed in 42 patients (76.3 percent) as compared with baseline measurement. The mean rectal stump flow reduction was 6.2 percent in patients without anastomotic leak, whereas in patients who developed anastomosis breakdown it was 16 percent (P<0.001). Mean proximal stump flow reduction was 5.1 percent in the uncomplicated patients, whereas in patients who had an anastomosis breakdown it was 12.9 percent (P<0.01). A positive linear correlation was found between decrease in blood flow and rate of anastomotic leak. CONCLUSION: Blood flow reduction at the rectal stump is associated with an increased risk of anastomotic leak.Presented in part at the XVII Biennial Congress of the International Society of University Colon and Rectal Surgeons, Malmö, Sweden, June 7 to 11, 1998.     

Successful treatment of autoimmune hepatitis and idiopathic thrombocytopenic purpura with the monoclonal antibody, rituximab: case report and review of literature.

Rituximab, a chimeric monoclonal anti-CD20 antibody, has shown activity in several autoimmune disorders. We describe a case of a 52 years old female who was diagnosed with idiopathic thrombocytopenic purpura and concomitant autoimmune hepatitis (AIH), both non-responsive to steroids. She was subsequently treated with rituximab, which resulted in a rapid increase in her platelet count and an unexpected normalization of her hepatic biochemical tests. Both her platelet count and her hepatic biochemical tests remained normal for over 5 months. In this case, rituximab showed an impressive clinical response for the treatment of AIH, and it may be considered as an alternative treatment in patients who do not respond to corticosteroid therapy. Prospective randomized studies in AIH are needed to validate this observation.     

Hemophagocytic lymphohistiocytosis associated with Leishmania: A hidden passenger in endemic areas

IntroductionHemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome characterized by excessive immune activation. We analyzed the presentation, diagnosis and prognosis of our cohort of HLH-Leishmania cases.MethodsWe studied HLH cases in patients over 14 years of age in the province of Granada (Spain), from January 2008 to November 2019.ResultsIn this study, Leishmania was the predominant trigger of adult HLH in our region. There were no differences in the clinical-analytical presentation between HLH triggered by Leishmania and those initiated by a different cause. RT-PCR was the best tool to identify Leishmania as the trigger of HLH, given that the other microbiological tests showed low sensitivity to detect the parasite in our HLH-Leishmania cases.ConclusionA comprehensive search for Leishmania is mandatory in HLH cases. Based on our findings, we propose that RT-PCR for Leishmania in bone marrow samples must be included in HLH differential diagnostic protocols.     

Maternal hyperthyroidism increases the prevalence of foregut atresias in fetal rats exposed to adriamycin

Purpose

Gastrointestinal malformations such as esophageal atresia with tracheoesophageal fistula (EA/TEF) and duodenal atresia (DA) have been reported in infants born to hyperthyroid mothers or with congenital hypothyroidism. The present study aimed to test whether maternal thyroid status during embryonic foregut division has any influence on the prevalence of EA/TEF and DA in an accepted rat model of these malformations.

Methods

Pregnant rats received either vehicle or 1.75 mg/kg i.p. adriamycin on gestational days 7, 8 and 9. Transient maternal hyper or hypothyroidism was induced by oral administration of levothyroxine (LT₄, 50 μg/kg/day) or propylthiouracil (PTU, 2 mg/kg/day), respectively, on days 7 to 12 of gestation. Plasma cholesterol, total T₃, free T₄ and TSH were measured at gestational days 7, 12, and 21. At the end of gestation, the mothers were sacrificed and embryo–fetal mortality was recorded. Fetuses were dissected to determine the prevalence of esophageal and intestinal atresias.

Results

At gestational day 12, mothers treated with LT₄ or PTU had hyper or hypothyroid status, respectively; plasma cholesterol levels were similar. In the adriamycin-exposed fetuses from hyperthyroid mothers, the embryonal resorption rate and the prevalence of both EA/TEF and DA were significantly higher than in the other groups; maternal hypothyroidism during the same period did not have significant effect on the prevalence of atresias.

Conclusions

Maternal hyperthyroidism during the embryonic window corresponding to foregut cleavage increased the prevalence of both EA/TEF and duodenal atresia in fetal rats exposed to adriamycin. This suggests that maternal thyroid hormone status might be involved in the pathogenesis of foregut atresias and invites further research on this likely clinically relevant issue in humans.     

CD38 expression in early B-cell precursors contributes to extracellular signal-regulated kinase-mediated apoptosis

CD38 is a 45 000 molecular weight transmembrane protein that is expressed in immature and mature lymphocytes. However, the expression and function of CD38 during B-cell differentiation in mice is poorly understood. Here, we report that CD38 is expressed from the earliest stages of B-cell development. Pre-pro-B, pro-B, pre-B and immature B cells from murine bone marrow all stained positive for CD38. Interestingly, CD38 expression increases with B-cell maturation. To assess the role of CD38 during B-cell maturation, CD38-deficient mice were analysed. CD38^−/− mice showed a significant increase in both the frequency of B-lineage cells and the absolute numbers of pre-pro-B cells in bone marrow; however, no other differences were observed at later stages. CD38 cross-linking in Ba/F3 cells promoted apoptosis and marked extracellular signal-regulated kinase (ERK) phosphorylation, and these effects were reduced by treatment with the mitogen-activated protein kinase/ERK kinase inhibitor PD98059, and similar effects were observed in B-cell precursors from bone marrow. These data demonstrate that B-cell precursors in mouse bone marrow express functional CD38 and implicate the early ligation of CD38 in the ERK-associated regulation of the B-lineage differentiation pathway.     

GLUT-1 overexpression: Link between hemodynamic and metabolic factors in glomerular injury?

Mesangial matrix deposition is the hallmark of hypertensive and diabetic glomerulopathy. At similar levels of systemic hypertension, Dahl salt-sensitive but not spontaneously hypertensive rats (SHR) develop glomerular hypertension, which is accompanied by upregulation of transforming growth factor beta1 (TGF-beta1), mesangial matrix expansion, and sclerosis. GLUT-1 is ubiquitously expressed and is the predominant glucose transporter in mesangial cells. In mesangial cells in vitro, GLUT-1 overexpression increases basal glucose transport, resulting in excess fibronectin and collagen production. TGF-beta1 has been shown to upregulate GLUT-1 expression. We demonstrated that in hypertensive Dahl salt-sensitive (S) rats fed 4% NaCl (systolic blood pressure [SBP]: 236+/-9 mm Hg), but not in similarly hypertensive SHR (SBP: 230+/-10 mm Hg) or their normotensive counterparts (Dahl S fed 0.5% NaCl, SBP: 145+/-5 mm Hg; and Wistar-Kyoto, SBP: 137+/-3 mm Hg), there was an 80% upregulation of glomerular GLUT-1 protein expression (P< or =0.03). This was accompanied by a 2.7-fold upregulation of TGF-beta1 protein expression in glomeruli of DSH compared with DSN rats (P=0.02). TGF-beta1 expression was not upregulated and did not differ in the glomeruli of Wistar-Kyoto and SHR rats. As an in vitro surrogate of the in vivo hemodynamic stress imposed by glomerular hypertension, we used mechanical stretching of human and rat mesangial cells. We found that after 33 hours of stretching, mesangial cells overexpressed GLUT-1 (40%) and showed an increase in basal glucose transport of similar magnitude (both P< or =0.01), which could be blocked with an anti TGF-beta1-neutralizing antibody. These studies suggest a novel link between hemodynamic and metabolic factors that may cooperate in inducing progressive glomerular injury in conditions characterized by glomerular hypertension.