Design of CD40 Agonists and Their Use in Growing B Cells for Cancer Immunotherapy

CD40 stimulation has produced impressive results in early-stage clinical trials of patients with cancer. Further progress will be facilitated by a better understanding of how the CD40 receptor becomes activated and the subsequent functions of CD40-stimulated immune cells. This review focuses on two aspects of this subject. The first is the recent recognition that signaling by CD40 is initiated when the receptors are induced to cluster within the membrane of responding cells. This requirement for CD40 clustering explains the stimulatory effects of certain anti-CD40 antibodies and the activity of many-trimer, but not one-trimer, forms of CD40 ligand (CD40L, CD154). The second topic is the use of these CD40 activators to expand B cells (“CD40-B cells”). As antigen-presenting cells (APCs), CD40-B cells are as effective as dendritic cells, with the important difference that CD40 B cells can be induced to proliferate in vitro, whereas DCs proliferate poorly if at all. As a result, the use of CD40-B cells as antigen-presenting cells (APCs) promises to streamline the generation of anti-tumor CD8⁺ T cells for the adoptive cell therapy (ACT) of cancer.     

Hydroxyethyl starch is an alternative washing solution for peripheral bloodstem cells products

Cryopreservation of hematopoietic stem cells (HSC) involves slow rate cooling in the presence of a cryoprotectant (DMSO) to avoid the damaging effects of intracellular ice formation. The infusion of DMSO with the thawed product has been related to adverse events. Reduction of DMSO content by washing the HSCs after thawing has been suggested as a method to avoid infusion-related side-effects. Albumin-dextran washing methods have proved useful in thawing HSC products. Dextran40 shortages prompted us to search for suitable alternatives. We report the results of a comparative study of the use of hydroxyethyl starch (HES) as an alternative to dextran40 for washing thawed HSCs products. A total of 10 HSC bags cryopreserved with 10 % DMSO were used. We conducted a paired study; one of the bags was thawed and washed with our standard washing solution (Dextran 40) and the paired bag with HES solution with a final HES and Human Serum Albumin (HSA) concentration of 2.4 % and 4.2 % respectively. Each final product was tested immediately after washing (sample 0’) and after 90 min (sample 90’) for total nucleated cells (TNC) recovery, acridine orange viability, viable CD34+ enumeration, and clonogenicity. No significant difference was found for any of the cell counts, viability tests, cell recovery, or potency. We can state that the washing solution based on 2.4 % HES and 4.2 % HSA is equivalent to that used in our routine practice. Therefore, we could use the solution with HES, paying special attention to the renal function of the recipient.     

Analysis of serum soluble CD40 ligand (sCD40L) in the patients undergoing allogeneic stem cell transplantation: platelet is a major source of serum sCD40L

CD40 ligand (CD40L) is expressed not only on activated T cells but also on activated platelets. A soluble CD40 ligand (sCD40L) is released from the activated T cells and platelets by ill-defined proteolytic process in vitro. It has been reported that sCD40L is elevated in the serum of patients with systemic lupus erythematosus, unstable angina, essential thrombocythemia, and autoimmune thrombocytopenic purupura. However, source of sCD40L in vivo remains to be elucidated. We investigated the serial sCD40L in the serum in patients undergoing allogeneic stem cell transplantation and compared with the platelets number and soluble IL2R, which is a marker of activated T cells. The value of sCD40L was well correlated with platelet number or thrombopoiesis. In cases of severe graft vs. host disease with markedly increased sIL2R, sCD40L was not increased in vivo. These results indicate that sCD40L in vivo is released mainly from the platelets or in the process of platelet production but not from the activated T cells.     

Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats

Aims/hypothesis Recent studies have shown that the inflammatory process is involved in the pathogenesis of diabetic nephropathy. Fourteen-membered ring macrolides, including erythromycin, have anti-inflammatory, as well as antibacterial effects. The aim of this study was to investigate the renoprotective effects of erythromycin in streptozotocin (STZ)-induced diabetic rats.Methods STZ-induced diabetic rats were treated orally with erythromycin (5 mg/kg body weight) or vehicle every day for 8 weeks. To evaluate the effect of erythromycin treatment, we measured urinary albumin excretion, and examined the following in the kidney: histological changes, the expression of intercellular adhesion molecule-1 (ICAM-1), macrophage infiltration, and nuclear factor-kappa B (NF-B) activity.Results Erythromycin significantly reduced urinary albumin excretion without affecting blood glucose levels and blood pressure. Erythromycin also attenuated glomerular hypertrophy, mesangial expansion, macrophage infiltration and ICAM-1 expression in renal tissues. The expression of the gene encoding TGFB1 (also known as TGF-1), type IV collagen protein production and NF-B activity in renal tissues were increased in diabetic rats and reduced by erythromycin treatment.Conclusions/interpretation Erythromycin prevented renal injuries without changes of blood glucose levels and blood pressure in experimental diabetic rats. These results suggest that the renoprotective effects of erythromycin are based on its anti-inflammatory effect via suppression of NF-B activation. Modulation of microinflammation with erythromycin may provide a new approach for diabetic nephropathy.     

CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma

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Implications of IL-13Rα2 in atopic skin inflammation

Atopic dermatitis (AD) is a common eczematous skin disorder characterized by skin inflammation, barrier disruption, chronic pruritus and marked scratching. Th2 cytokines, especially IL-13, play a pathogenic role in AD. IL-13 signals via a heterodimeric receptor composed of IL-4Rα and IL-13 Rα1. A second receptor, IL-13 Rα2, binds to IL-13 with high affinity, but it works as a decoy receptor. IL-13 Rα2 is overexpressed in the lesional skin of AD. Notably, mechanical scratching, as well as IL-13 itself, also upregulates IL-13 Rα2 expression. The scratch-induced IL-13 Rα2 upregulation may attenuate the IL-13-mediated epidermal barrier dysfunction and dermal fibrosis. Recent studies stress an importance of another IL-13 Rα2 ligand, chitinase 3-like 1 or YKL-40 in Th2 differentiation. However, the implications of increased IL-13 Rα2 levels remain elusive in AD. In this review, we summarize the recent topics on IL-13 Rα2 in atopic skin inflammation.