CD72-semaphorin3A axis: A new regulatory pathway in systemic lupus erythematosus.

CD72 is a regulatory co-receptor on B cells, with a role in the pathogenesis of systemic lupus erythematosus (SLE) in both human and animal models. Semaphorin3A (sema3A) is a secreted member of the semaphorin family that can reconstruct B cells' regulatory functions by upregulating IL-10 expression and inhibiting the pro-inflammatory activity of B and T cells in autoimmune diseases. The aim of our present study was to identify a new ligand for CD72, namely sema3A, and exploring the signal transduction pathways following its ligation in B cells. We established that CD72 functions as sema3A binding and signal-transducing receptor. These functions of CD72 are independent of neuropilin-1 (NRP-1) (the known sema3A receptor). We discovered that sema3A induces the phosphorylation of CD72 on tyrosine residues and the association of CD72 with SHP-1 and SHP-2. In addition, the binding of sema3A to CD72 on B cells inhibits the phosphorylation of STAT-4 and HDAC-1 and induces the phosphorylation of p38-MAPK and PKC-theta in B-cells derived B-lymphoblastoid (BLCL) cells, and in primary B-cells isolated from either healthy donors or SLE patients. We concluded that sema3A is a functional regulatory ligand for CD72 on B cells. The sema3A-CD72 axis is a crucial regulatory pathway in the pathogenesis of autoimmune and inflammatory diseases namely SLE, and modulation of this pathway may have a potential therapeutic value for autoimmune diseases.

New biologics in the treatment of urticaria.

PURPOSE OF REVIEW: Symptomatic management of chronic spontaneous urticaria (CSU) basically depends on second-generation H1 antihistamines and omalizumab. Omalizumab is a game changer in the management, but still there is a need for new targets and new biologics targeting new pathways in the treatment which will provide long-lasting remission, which will be given orally and which will be cheaper. This review will focus on new biologics that are underway of production or are already under use for different disorders but could be beneficial for the treatment of Chronic urticaria. RECENT FINDINGS: In this review, the treatment targets are classified according to the cells which are involved in the pathogenesis of CSU. Those are mast cells/basophils, B cells, T cells and eosinophils. The treatments that are under clinical trials for CSU are anti-IgE treatments such as ligelizumab, molecules targeting intracellular signaling pathways such as spleen tyrosine kinase inhibitors, surface inhibitory molecules such as siglec-8, anti-IL-1s such as canakinumab, Bruton kinase (BTK) inhibitors such as GDC-0853 and anti-IL-5s such as benralizumab and mepolizumab. SUMMARY: The ongoing clinical trials on new targets of treatment hold new hopes not only for a better care of the disease but also a better understanding of the pathomechanisms lying underneath.

Design of a ProDer f 1 vaccine delivered by the MHC class II pathway of antigen presentation and analysis of the effectiveness for specific immunotherapy.

Dermatophagoides farinae (Der f 1) is one of leading cause for allergic asthma, and allergen-specific immunotherapy (SIT) is currently recognized as the only etiological therapy to ameliorate asthmatic symptom. The current study was designed on the major histocompatibility complex (MHC) class II pathway, invariant chain (Ii)-segment hybrids as vaccine basis to explore the efficacy of Der f 1 hybrid vaccine by virtue of Ii as carrier in enhancing the protective immune response to asthma. Initially, we engineered a fused molecule, DCP-IhC-ProDer f 1, to deliver ProDer f 1 antigen via specific dendritic cell-targeting peptides to dendritic cells (DCs). Then the DCP-IhC-ProDer f 1 was immunized to the asthmatic models of murine induced by ProDer f 1 allergen. The findings showed that the cytokine repertoire in the murine model was shifted after SIT, including stronger secretion of IFN-γ and IL-10, and a decreased production of IL-4 and IL-17. ELISA determination revealed that the hybrid displayed weak IgE and IgG1 reactivities, and IgG2a levels were elevated. Furthermore, DCP-IhC-ProDer f 1 treatment inhibited inflammatory cell infiltration in the lung tissues. Our results suggest that the DCP-Ihc-ProDer f 1 may be used as a candidate SIT against asthma.

Fusion of HCV nonstructural antigen to MHC class II-associated invariant chain enhances T-cell responses induced by vectored vaccines in nonhuman primates.

Despite viral vectors being potent inducers of antigen-specific T cells, strategies to further improve their immunogenicity are actively pursued. Of the numerous approaches investigated, fusion of the encoded antigen to major histocompatibility complex class II-associated invariant chain (Ii) has been reported to enhance CD8(+) T-cell responses. We have previously shown that adenovirus vaccine encoding nonstructural (NS) hepatitis C virus (HCV) proteins induces potent T-cell responses in humans. However, even higher T-cell responses might be required to achieve efficacy against different HCV genotypes or therapeutic effect in chronically infected HCV patients. In this study, we assessed fusion of the HCV NS antigen to murine and human Ii expressed by the chimpanzee adenovirus vector ChAd3 or recombinant modified vaccinia Ankara in mice and nonhuman primates (NHPs). A dramatic increase was observed in outbred mice in which vaccination with ChAd3 expressing the fusion antigen resulted in a 10-fold increase in interferon-γ(+) CD8(+) T cells. In NHPs, CD8(+) T-cell responses were enhanced and accelerated with vectors encoding the Ii-fused antigen. These data show for the first time that the enhancement induced by vector vaccines encoding li-fused antigen was not species specific and can be translated from mice to NHPs, opening the way for testing in humans.

Ii-Key/HPV16 E7 hybrid peptide immunotherapy for HPV16+ cancers.

Activation of antigen-specific CD4+ T cells is critical for vaccine design. We have advanced a novel technology for enhancing activation of antigen-specific CD4+ T helper cells whereby a fragment of the MHC class II-associated invariant chain (Ii-Key) is linked to an MHC class II epitope. An HLA-DR4-restricted HPV16 E7 epitope, HPV16 E7(8-22), was used to create a homologous series of Ii-Key/HPV16 E7 hybrids testing the influence of spacer length on in vivo enhancement of HPV16 E7(8-22)-specific CD4+ T lymphocyte responses. HLA-DR4-tg mice were immunized with Ii-Key/HPV16 E7(8-22) hybrids or the epitope-only peptide HPV16 E7(8-22). As measured by IFN-gamma ELISPOT assay of splenocytes from immunized mice, one of the Ii-Key/HPV16 E7(8-22) hybrids enhanced epitope-specific CD4+ T cell activation 5-fold compared to the HPV16 E7(8-22) epitope-only peptide. We further demonstrated that enhanced CD4+ T cell activation augments the CTL activity of a H-2D(b)-restricted HPV16 E7(49-57) epitope in HLA-DR4+ mice using an in vivo CTL assay. Binding assays indicated that the Ii-Key/HPV16 hybrid has increased affinity to HLA-DR4+ cells relative to the epitope-only peptide, which may explain its increased potency. In summary, Ii-Key hybrid modification of the HLA-DR4-restricted HPV16 E7(8-22) MHC class II epitope generates a potent immunotherapeutic peptide vaccine that may have potential for treating HPV16+ cancers in HLA-DR4+ patients.

Experimental therapy of disseminated B-Cell lymphoma xenografts with 213Bi-labeled anti-CD74.

A (213)Bi-labeled antibody to CD74 was evaluated as a therapeutic agent for B-cell lymphoma. The alpha-particle emission, with a half-life of 46 min, is appropriate for therapy of micrometastases. The labeled Ab retained full immunoreactivity, and was potent at single-cell kill of the Raji B-lymphoma cell line. Approximately 30 decays of cell-bound (213)Bi was required for a cell kill of 99%, and dosimetry calculations suggested that the cGy dose delivered was sufficient to produce the level of toxicity observed. A non-reactive control Ab, labeled similarly, also produced toxicity, due to decays occurring in the medium, but was approximately 3-fold less potent than the reactive Ab. In a SCID mouse xenograft micrometastatic model, Ab injection at day 2 or day 5 after tumor inoculation resulted in strong, specific suppression of tumor growth, with some apparent cures.