10 research outputs found
Uptake of Leishmania major by dendritic cells is mediated by FcĪ³ receptors and facilitates acquisition of protective immunity
Uptake of Leishmania major by dendritic cells (DCs) results in activation and interleukin (IL)-12 release. Infected DCs efficiently stimulate CD4ā and CD8ā T cells and vaccinate against leishmaniasis. In contrast, complement receptor 3ādependent phagocytosis of L. major by macrophages (MĪ¦) leads exclusively to MHC class IIārestricted antigen presentation to primed, but not naive, T cells, and no IL-12 production. Herein, we demonstrate that uptake of L. major by DCs required parasite-reactive immunoglobulin (Ig)G and involved FcĪ³RI and FcĪ³RIII. In vivo, DC infiltration of L. majorāinfected skin lesions coincided with the appearance of antibodies in sera. Skin of infected B cellādeficient mice and FcĪ³ā/ā mice contained fewer parasite-infected DCs in vivo. Infected B cellādeficient mice as well as FcĪ³ā/ā mice (all on the C57BL/6 background) showed similarly increased disease susceptibility as assessed by lesion volumes and parasite burdens. The B cellādeficient mice displayed impaired T cell priming and dramatically reduced IFN-Ī³ production, and these deficits were normalized by infection with IgG-opsonized parasites. These data demonstrate that DC and MĪ¦ use different receptors to recognize and ingest L. major with different outcomes, and indicate that B cellāderived, parasite-reactive IgG and DC FcĪ³RI and FcĪ³RIII are essential for optimal development of protective immunity
Critical role of IL-10 in the induction of low zone tolerance to contact allergens
The development and mechanisms of tolerance to allergens are poorly understood. Using the murine low zone tolerance (LZT) model, where contact hypersensitivity (CHS) is prevented by repeated topical low-dose applications of contact allergens, we show that LZT induction is IL-10 dependent. IL-10 is required for the generation of LZT effector cells, that is, CD8(+) regulatory T cells. Only T cells from tolerized IL-10(+/+) mice or IL-10(ā/ā) mice reconstituted with IL-10 during LZT induction adoptively transferred LZT to naive mice and prevented CHS, whereas T cells from IL-10(ā/ā) mice failed to do so. The IL-10 required for normal LZT development is derived from lymph node CD4(+) T cells, the only skin or lymph node cell population found to produce relevant amounts of IL-10 after tolerization. CD4(+) T cells derived from IL-10(+/+) mice, but not from IL-10(ā/ā) mice, allowed the induction of LZT in adoptively transferred T cellādeficient mice. Interestingly, IL-10 injections during tolerization greatly enhanced LZT responses in normal mice. Thus, the generation of CD8(+) LZT effector T cells by CD4(+) regulatory T cells via IL-10 may be a promising target of strategies aimed at preventing contact allergies and other harmful immune responses
CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed Multiple Myeloma
C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM).
Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival.
ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive.
CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted
Genetic variants of folate and methionine metabolism and PCNSL incidence in a German patient population
Functional genetic polymorphisms involved in folate and methionine metabolism play an important role in both DNA synthesis and methylation, and affect the risk of various malignancies including lymphoproliferative disorders such as systemic non-Hodgkin's lymphoma. In a retrospective analysis of 185 immunocompetent patients with primary central nervous system lymphoma (PCNSL) and 212 population controls we therefore investigated eight genetic polymorphisms affecting methionine metabolism for potential association with the development of PCNSL. We observed underrepresentation of the G-allele of the methyltetrahydrofolate homocysteine S-methyltransferase (MTR) c.2756A > G (D919G) missense polymorphism among PCNSL patients (P = 0.045; odds ratio (OR) = 0.65; 0.43-0.99). Furthermore, for the methylenetetrahydrofolate reductase (MTHFR) c.1298A > C (E429A) polymorphism the mutated C-allele was found more frequently among PCNSL patients than among population controls (P = 0.026; OR = 1.57; 1.05-2.34). There were no associations of the other polymorphisms investigated (MTHFR c.677C > T, transcobalamin 2 (Tc2) c.776C > G, cystathionin beta-synthase (CBS) c.844_855ins68, reduced folate carrier-1 (RFC-1) c.80G > A, thymidylate synthase (TYMS) 28-bp repeat, and dihydrofolate reductase (DHFR) c.594 + 59del19 bp) and the presence of PCNSL. This analysis is the largest to date to evaluate associations between genetic variants of folate and methionine metabolism and PCNSL. Our results suggest the hypothesis that folate and methionine metabolism is relevant to susceptibility to PCNSL
Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine
Epigenetic processes, such as DNA methylation, and molecular chaperones,
including FK506-binding protein 51 (FKBP51), are independently
implicated in stress-related mental disorders and antidepressant drug
action. FKBP51 associates with cyclin-dependent kinase 5 (CDK5), which
is one of several kinases that phosphorylates and activates DNA
methyltransferase 1 (DNMT1). We searched for a functional link between
FKBP51 (encoded by FKBP5) and DNMT1 in cells from mice and humans,
including those from depressed patients, and found that FKBP51 competed
with its close homolog FKBP52 for association with CDK5. In human
embryonic kidney (HEK) 293 cells, expression of FKBP51 displaced FKBP52
from CDK5, decreased the interaction of CDK5 with DNMT1, reduced the
phosphorylation and enzymatic activity of DNMT1, and diminished global
DNA methylation. In mouse embryonic fibroblasts and primary mouse
astrocytes, FKBP51 mediated several effects of paroxetine, namely,
decreased the protein-protein interactions of DNMT1 with CDK5 and
FKBP52, reduced phosphorylation of DNMT1, and decreased the methylation
and increased the expression of the gene encoding brain-derived
neurotrophic factor (Bdnf). In human peripheral blood cells, FKBP5
expression inversely correlated with both global and BDNF methylation.
Peripheral blood cells isolated from depressed patients that were then
treated ex vivo with paroxetine revealed that the abundance of BDNF
positively correlated and phosphorylated DNMT1 inversely correlated with
that of FKBP51 in cells and with clinical treatment success in patients,
supporting the relevance of this FKBP51-directed pathway that prevents
epigenetic suppression of gene expression