ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid or myeloid cells surface antigens [II]: CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4).

BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of agents targeting CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4 and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: The risk and spectrum of infections in patients receiving CD22-targeted agents (i.e. inotuzumab ozogamicin) are similar to those observed with anti-CD20 antibodies. Anti-Pneumocystis prophylaxis and monitoring for cytomegalovirus (CMV) infection is recommended for patients receiving CD30-targeted agents (brentuximab vedotin). Due to the scarcity of data, the risk posed by CD33-targeted agents (gemtuzumab ozogamicin) cannot be assessed. Patients receiving CD38-targeted agents (i.e. daratumumab) face an increased risk of varicella-zoster virus (VZV) infection. Therapy with CD40-targeted agents (lucatumumab or dacetuzumab) is associated with opportunistic infections similar to those observed in hyper-IgM syndrome, and prevention strategies (including anti-Pneumocystis prophylaxis and pre-emptive therapy for CMV infection) are warranted. SLAMF-7 (CD319)-targeted agents (elotuzumab) induce lymphopenia and increase the risk of infection (particularly due to VZV). The impact of CCR4-targeted agents (mogamulizumab) on infection susceptibility is difficult to distinguish from the effect of underlying diseases and concomitant therapies. However, anti-Pneumocystis and anti-herpesvirus prophylaxis and screening for chronic hepatitis B virus (HBV) infection are recommended. IMPLICATIONS: Specific management strategies should be put in place to reduce the risk and/or the severity of infectious complications associated to the reviewed agents.

Tanshinone IIA downregulates the CD40 expression and decreases MMP-2 activity on atherosclerosis induced by high fatty diet in rabbit.

Tanshinone IIA (Tan IIA) is a member of the major lipophilic components abstracted from the root of Salvia miltiorrhiza Bunge and has the capacity of anti-atherosclerosis. To investigate the potential mechanism, we established an animal model by giving high fatty diet to rabbits and Tan IIA was given in different dose. Then, superoxide dismutase (SOD) activity and the malondialdehyde (MDA) level in serum were detected using spectrophotometry; cluster of differentiation 40 (CD40) expression of cellular membrane fraction of aortas and matrix metalloproteinase-2 (MMP-2) activity of total protein extract of aortas were detected by Western Blotting and Zymography, respectively. Compared with the control group, the level of MDA, the expression of CD40 and the MMP-2 activity were increased while the SOD activity was decreased significantly in model group. After Tan IIA administration, the SOD activity was significantly increased while the level of MDA was decreased; both the expression of CD40 and the activity of MMP-2 were decreased. It is suggested that Tan IIA not only inhibits the oxidation but also suppresses the inflammation in atherosclerotic lesion. Our data suggest that not only anti-oxidation but also anti-inflammation by decrease the expression of CD40 and MMP-2 activity maybe the potential mechanisms by which Tan IIA anti-atherosclerosis.

Honokiol, a natural plant product, inhibits inflammatory signals and alleviates inflammatory arthritis.

Honokiol (HNK), a phenolic compound isolated and purified from magnolia, has been found to have a number of pharmacologic benefits, including anti-angiogenic and anti-inflammatory properties. HNK has long been used in traditional Asian medicine without toxic side effects. We and others have extensively studied signaling to B cells by CD40 and its Epstein Barr viral mimic, latent membrane protein 1 (LMP1), which has been implicated in exacerbation of chronic autoimmune disease. We asked whether HNK could inhibit CD40 and LMP1 inflammatory signaling mechanisms. In vivo, HNK stabilized the severity of symptomatic collagen-induced arthritis in both CD40-LMP1 transgenic mice and their congenic C57BL/6 counterparts. Ex vivo studies, including collagen-specific serum Ab and Ag recall responses, as well as CD40 or LMP1-mediated activation of splenic B cells, supported the anti-inflammatory effects of HNK. In mouse B cell lines expressing the human CD40-LMP1 chimeric receptor, CD40- and LMP1-mediated NF-kappaB and AP-1 activation were abrogated in a dose-dependent manner, with a concomitant decrease in TNF-alpha and IL-6. These promising findings suggest that the nontoxic anti-inflammatory properties of HNK could be valuable for blocking the autoimmune response.

Polyphenolic antioxidants inhibit peptide presentation by antigen-presenting cells.

Antigen-presenting cells (APC) provide two essential signals, e.g., antigenic peptides as well as costimulatory molecules for T-cell activation. Small molecules of smoke tobacco extracts (SM-STE) inhibited antigen presentation of A20 to OVAp-specific T-cell hybridomas. Pretreatment of A20 but not T hybridomas abrogates the APC function. Viability of APC and levels of MHCII, CD40 and B7 of APC were not affected by this treatment. The active principle, inhibiting APC was reproduced with pure tobacco polyphenols, quercetin and its glycoside, rutin. Antioxidant activity of rutin is relevant since rutin downregulated levels of reactive oxygen species (ROS) in phorbol ester-stimulated A20; moreover, another antioxidant, N-acetyl cysteine (NAC) also inhibited antigen presentation, albeit at a higher concentration. Other types of APC, such as bone marrow-derived mast cells (BMMC), MHCII-transfected fibroblast, and splenocytes are affected by tobacco polyphenols. We propose that polyphenols may affect redox-sensitive signal transduction pathway since APC function of PD 98059, MEK inhibitor-pretreated A20 were similarly abrogated. Taken together, we propose that maintaining appropriate intracellular redox of APC is crucial for its antigen-presenting function.

Differential regulatory effects of cAMP-elevating agents on human normal and neoplastic B cell functional response following ligation of surface immunoglobulin and CD40.

The B cell response to ligation of surface immunoglobulin (sIg) and CD40 is dependent on the stage of cellular differentiation of the population studied. Cross-linking sIg promotes proliferation of follicular mantle (FM) B cells, rescues germinal center (GC) B cells from spontaneous apoptosis but induces apoptosis in susceptible Burkitt lymphoma (BL) B cells; signals transduced through CD40 induce resting FM B cells to enter cell cycle while promoting GC and BL B cell survival. This study investigates whether the 3', 5'-cyclic adenosine monophosphate (cAMP)-dependent second-messenger pathway plays a role in the regulation of these sIg- and CD40-promoted B cell responses, using prostaglandin E2 (PGE2) and forskolin to artificially increase intracellular levels of cAMP. The Epstein-Barr virus (EBV)-genome-negative BL B cell line Ramos is susceptible to growth arrest and apoptosis triggered by calcium ionophore, anti-IgM and forskolin but not by PGE2; forskolin does not affect the outcome of anti-IgM treatment. Anti-CD40 rescues Ramos-BL B cells from ionophore- and anti-IgM-triggered but not forskolin-triggered growth arrest and apoptosis; moreover, forskolin and anti-CD40 act additively and independently for enhanced growth inhibition. By contrast, both forskolin and PGE2 potentiate the proliferative response of FM B cells cultured with anti-Ig and anti-CD40 together but not individually. Forskolin and PGE2 fail to affect the spontaneous apoptosis and anti-Ig- and anti-CD40-promoted survival of GC B cells. Thus, the cAMP-dependent second messenger pathway can differentially influence the BL, FM, and GC B cell functional response to signals transduced through sIg and CD40.