Abstract While studying Th responses induced by cardiac transplantation, we observed that mice deficient in the Th1 transcription factor T-bet (T-bet−/−) mount both and Th17 responses, whereas wild-type recipients only responses. Cells producing IFN-γ IL-17 were readily detectable within rejecting graft of T-bet−/− recipients, but absent from spleen, indicating vivo microenvironment influences function. In addition, disrupting CD40-CD40L costimulatory interactions was highly effective at...

Nasal-associated lymphoid tissue (NALT), a mucosal inductive site for the upper respiratory tract, is important development of immunity locally and distally to intranasally introduced Ag. To more fully understand induction nasal immunity, we investigated addressins that allow lymphocyte trafficking this tissue. investigate responsible naive binding, immunofluorescent immunoperoxidase staining frozen NALT sections were performed using anti-mucosal addressin cell adhesion molecule-1...

DNA immunization, although attractive, is poor for inducing mucosal immunity, thus limiting its protective value against most infectious agents. To surmount this shortcoming, we devised a method transgene vaccination by using an M cell ligand to direct the vaccine inductive tissues and respiratory epithelium. This ligand, reovirus protein σ1, when conjugated polylysine (PL), can bind apical surface of cells from nasal-associated lymphoid tissues. Intranasal immunizations with σ1-PL-DNA...

Cardiac transplantation is an effective treatment for multiple types of heart failure refractive to therapy. Although immunosuppressive therapeutics have increased survival rates within the first year posttransplant, chronic rejection (CR) remains a significant barrier long-term graft survival. Indicators CR include patchy interstitial fibrosis, vascular occlusion and progressive loss function. Multiple factors been implicated in onset progression CR, including TGFbeta, IL-6 connective...

<b><i>Objective:</i></b> Chronic inflammatory processes contribute to the eventual death of motor neurons and development symptoms in both idiopathic Parkinson disease (PD) multiple system atrophy (MSA). Given faster rate progression more severe associated with MSA, we hypothesized that markers inflammation would be evident peripheral blood MSA than PD patients, evidence this might assist early diagnosis versus PD. <b><i>Methods:</i></b> We...

The head and neck lymph nodes (LN)--or cranial, oral, nasal-associated lymphoid tissue (CONALT)--help disseminate activated lymphocytes to produce salivary immune responses, especially after intranasal immunization. To elucidate the mechanisms that induce immunity at these sites, we investigated interactions between addressins homing-receptors allow for lymphocyte binding high endothelial venules (HEV) of CONALT. In vivo trafficking CONALT was mediated primarily through peripheral node...

Late loss of allograft function is primarily attributed to chronic rejection (CR). There are no effective treatments for CR and the underlying cause disease unknown. This study compared events that occurred within cardiac allografts placed in mice received either anti-CD4 therapy develop or anti-CD40L do not CR. Both TGFbeta connective tissue growth factor (CTGF), which induced by TGFbeta, were expressed grafts with but without transfection anti-CD40L-treated recipients resulted CTGF...

Abstract Neutrophils are a type of granulocyte important in the “first line defense” innate immune system. Upon activation, they facilitate destruction invading microorganisms by production superoxide radicals, as well release enzymatic contents their lysozymes. These enzymes include specific serine proteases: cathepsin G, neutrophil elastase, proteinase 3, recently discovered protease 4 (NSP4). Under normal conditions, proteolytic activity proteases is tightly regulated endogenous serpins;...

Cutaneous neurofibromas cause disfigurement and discomfort in individuals with neurofibromatosis type 1 (NF-1). The primary objective of this phase II, open-label, single-arm trial was to assess whether orally administered everolimus reduced the surface volume cutaneous patients NF-1. Of 22 who took study drug, 17 completed trial; 5 withdrew due adverse events. Sixteen had photographs sufficient quality for assessment outcome. A significant reduction lesion volume, defined as an end > 2...

Abstract The common mucosal immune system may be compartmentalized because lymphocyte homing to the upper respiratory tract appears mediated by L-selectin interactions rather than α4β7 interactions, as is case for gut-associated lymphoreticular tissue. To assess role of in effector B cell immunity, L-selectin-deficient mice were intranasally immunized with cholera toxin (CT), and responses compared C57BL/6 mice. absence correlated a reduction CT-specific secretory-IgA nasal passages...

Adenovirus‐mediated transfection of mouse cardiac allografts with active human transforming growth factor‐beta 1 (TGF‐β1) prolongs transplant survival provided that recipients are initially depleted CD8+ T cells. To test if graft was prolonged by persistent TGF‐β1 transgene expression, long‐term transfected were re‐transplanted into naïve mice transiently Re‐transplanted acutely rejected, indicating expression did not suppress effector cell function. We next asked whether gene transfer...

It has been proposed that resistance to rapalog therapies in renal cell carcinoma (RCC) is due adaptive switching from mammalian target of rapamycin complex 1 (mTORC1) mTORC2.To combine phosphoprotein staining and applied biomedical analytics investigate signatures patients with metastatic RCC progressing on therapies.We morphoproteomic analysis biopsy specimens nine who continued show clinical progression their tumors while being treated a rapalog.In were temsirolimus or everolimus at the...

Abstract Previous studies suggest that lymphocyte trafficking to head and neck lymph nodes, also referred as cranial-, oral-, nasal-associated lymphoid tissue (CONALT), is L-selectin (L-Sel) dependent, despite coexpression of α4β7, resulting in their marked reduction L-Sel-deficient (L-Sel−/−) mice. Consequently, early phase (16 days) Ab responses cholera toxin (CT) are diminished. The following reveal lack mucosal effector not caused by loss inductive immune the L-Sel−/− CONALT. Indeed,...

CD4(+) T cells that respond to indirectly presented alloantigen have been shown mediate chronic rejection, however, the role of indirect pathway in acute rejection has yet be completely elucidated. To this end, BALB/c or C57BL/6 mice were depleted CD8(+) and transplanted with class II transactivator (CIITA)-deficient cardiac allografts, which cannot directly present alloantigens cells. In manner, response by was forced rely upon recognition pathway. When not cells, both rejected CIITA-/-...

Abstract Costimulation through the CD40-CD40 ligand (CD40L) pathway is critical to allograft rejection, in that anti-CD40L mAb therapy prolongs survival. However, majority of studies exploring CD40-CD40L interactions have targeted CD40L. Less known about requirement for donor- and/or host-derived CD40 during rejection. This study assessed relative contributions donor and recipient expression rejection process. As effectiveness costimulatory blockade may be mouse strain dependent, this...

Understanding the role of homing receptors could aid vaccine strategies for developing distal mucosal immunity. Infection studies have revealed that immune intestinal B cells use alpha(4)beta(7) receptors, but their in subsequent oral immunization with soluble antigens is unknown. To assess influence L-selectin and on following cholera toxin (CT) immunization, L-selectin-deficient (L-Sel(-/-)) IgA anti-CT-B-specific were enhanced 30-, 9.2-, 3.5-fold head neck lymph nodes (HNLNs),...

Hemophilia A is a congenital bleeding disorder caused by defective or deficient factor VIII (FVIII). The active form of FVIII the co-factor for serine protease IXa (FIXa) in membrane-bound intrinsic tenase (FVIIIa-FIXa) complex. assembly FVIIIa-FIXa complex on activated platelet surface critical successful blood clotting.To characterize role lipid nanodiscs (ND) function vivo and test ND as delivery system FVIII. To evaluate potential binding recombinant to improved treatment A.Recombinant...

CD40-CD40L blockade has potent immunosuppressive effects in cardiac allograft rejection but is less effective the presence of inflammatory signals. To better understand factors that mediate blockade-resistant rejection, we studied stimulation through glucocorticoid-induced TNFR-related protein (GITR), a costimulatory expressed by regulatory and effector T cells. Stimulation CD40-/- or wild-type recipient mice treated with anti-CD40L mAb (WT+anti-CD40L) agonistic anti-GITR resulted rejection....

The antigen-binding sites of antibodies (Abs) can express enzyme-like nucleophiles that react covalently with electrophilic compounds. We examined the irreversible and specific inactivation to Factor VIII (FVIII) responsible for failure FVIII replacement therapy in hemophilia A (HA) patients. Electrophilic analogs (E-FVIII) its C2 domain (E-C2) were prepared by placing strongly phosphonate groups at surface-exposed Lys side chains diverse antigenic epitopes. IgG Abs from HA patients formed...