Daratumumab, a human monoclonal antibody that targets CD38, depletes plasma cells and is approved for the treatment of multiple myeloma. Long-lived plasma cells are implicated in the pathogenesis of systemic lupus erythematosus because they secrete autoantibodies, but they are unresponsive to standard immunosuppression. We describe the use of daratumumab that induced substantial clinical responses in two patients with life-threatening lupus, with the clinical responses sustained by maintenance therapy with belimumab, an antibody to B-cell activating factor. Significant depletion of long-lived plasma cells, reduction of interferon type I activity, and down-regulation of T-cell transcripts associated with chronic inflammation were documented. (Supported by the Deutsche Forschungsgemeinschaft and others.)

The co-stimulators ICOS (inducible T cell co-stimulator) and CD28 are both important for T follicular helper (TFH) cells, yet their individual contributions are unclear. Here, we show that each molecule plays an exclusive role at different stages of TFH cell development. While CD28 regulated early expression of the master transcription factor Bcl-6, ICOS co-stimulation was essential to maintain the phenotype by regulating the novel TFH transcription factor Klf2 via Foxo1. Klf2 directly binds to Cxcr5, Ccr7, Psgl-1, and S1pr1, and low levels of Klf2 were essential to maintain this typical TFH homing receptor pattern. Blocking ICOS resulted in relocation of fully developed TFH cells back to the T cell zone and reversion of their phenotype to non-TFH effector cells, which ultimately resulted in breakdown of the germinal center response. Our study describes for the first time the exclusive role of ICOS and its downstream signaling in the maintenance of TFH cells by controlling their anatomical localization in the B cell follicle.

Patients with kidney failure are at increased risk of SARS-CoV-2 infection, making effective vaccinations a critical need. It is not known how well mRNA vaccines induce B and plasma cell responses in dialysis patients (DPs) or kidney transplant recipients (KTRs) compared with healthy controls (HCs). We studied humoral and B cell responses of 35 HCs, 44 DPs, and 40 KTRs. Markedly impaired anti-BNT162b2 responses were identified among KTRs and DPs compared with HCs. In DPs, the response was delayed (3 to 4 weeks after boost) and reduced with anti-S1 IgG and IgA positivity in 70.5 and 68.2%, respectively. In contrast, KTRs did not develop IgG responses except for one patient who had a previous unrecognized infection and developed anti-S1 IgG. Most antigen-specific B cells (RBD⁺) were identified in the plasmablast or post-switch memory B cell compartments in HCs, whereas RBD⁺ B cells were enriched among pre-switch and naïve B cells from DPs and KTRs. The frequency and absolute number of antigen-specific circulating plasmablasts in the cohort correlated with the Ig response, a characteristic not reported for other vaccinations. In conclusion, these data indicated that immunosuppression resulted in impaired protective immunity after mRNA vaccination, including Ig induction with corresponding generation of plasmablasts and memory B cells. Thus, there is an urgent need to improve vaccination protocols in patients after kidney transplantation or on chronic dialysis.