Regulated Expansion and Survival of Chimeric Antigen Receptor-Modified T Cells Using Small Molecule-Dependent Inducible MyD88/CD40.

Anti-tumor efficacy of T cells engineered to express chimeric antigen receptors (CARs) is dependent on their specificity, survival, and in vivo expansion following adoptive transfer. Toll-like receptor (TLR) and CD40 signaling in T cells can improve persistence and drive proliferation of antigen-specific CD4 and CD8 T cells following pathogen challenge or in graft-versus-host disease (GvHD) settings, suggesting that these costimulatory pathways may be co-opted to improve CAR-T cell persistence and function. Here, we present a novel strategy to activate TLR and CD40 signaling in human T cells using inducible MyD88/CD40 (iMC), which can be triggered in vivo via the synthetic dimerizing ligand, rimiducid, to provide potent costimulation to CAR-modified T cells.

Airway surface mycosis in chronic TH2-associated airway disease.

Background: Environmental fungi have been linked to TH2 cell-related airway inflammation and the TH2-associated chronic airway diseases asthma, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), and allergic fungal rhinosinusitis (AFRS), but whether these organisms participate directly or indirectly in disease pathology remains unknown.

Objective: To determine the frequency of fungus isolation and fungus-specific immunity in patients with TH2-associated and non-TH2-associated airway disease.

Methods: Sinus lavage fluid and blood were collected from sinus surgery patients (n = 118) including patients with CRSwNP, patients with CRS without nasal polyps, patients with AFRS, and non-CRS/nonasthmatic control patients.

IL-33-responsive innate lymphoid cells are an important source of IL-13 in chronic rhinosinusitis with nasal polyps.

Rationale: Chronic rhinosinusitis (CRS) without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP) are associated with Th1 and Th2 cytokine polarization, respectively; however, the pathophysiology of CRS remains unclear. The importance of innate lymphoid cells in Th2-mediated inflammatory disease has not been clearly defined.

Objectives: The objective of this study was to investigate the role of the epithelial cell-derived cytokine IL-33 and IL-33-responsive innate lymphoid cells in the pathophysiology of CRS.

Increased percentage of mast cells within sinonasal mucosa of chronic rhinosinusitis with nasal polyp patients independent of atopy.

Background: Initial attention on the pathophysiology of chronic rhinosinusitis (CRS) has focused on eosinophils. Other immune cells such as mast cells (MCs) have been identified and appear to be elevated in CRS with nasal polyp (NP) patients. MCs are commonly linked to immunoglobulin E (IgE)-mediated inflammatory changes characterized by elevated T helper 2 cytokines.

Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus.

Human thymus contains major dendritic cell (DC) subsets, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs). We previously showed that mDCs, educated by thymic stromal lymphopoietin (TSLP) produced by the epithelial cells of the Hassall's corpuscles, induced differentiation of CD4(+)CD25(-) thymocytes into Forkhead Box P3(+) (FOXP3(+)) regulatory T cells (T(R)) within the medulla of human thymus. In this study, we show that pDCs expressed the TSLP receptor and IL-7 receptor alpha complexes upon activation and became responsive to TSLP.

Regulation of TLR7/9 responses in plasmacytoid dendritic cells by BST2 and ILT7 receptor interaction.

Plasmacytoid dendritic cells (pDCs) produce copious type I interferon (IFN) upon sensing nucleic acids through Toll-like receptor (TLR) 7 and TLR9. Uncontrolled pDC activation and IFN production are implicated in lymphopenia and autoimmune diseases; therefore, a mechanism controlling pDC IFN production is essential. Human pDCs specifically express an orphan receptor, immunoglobulin-like transcript 7 (ILT7).

Hematopoietic stem cell recipients do not develop post-transplantation immune tolerance to antigens present on minimal residual disease.

The immune environment present after allogeneic hematopoietic stem cell transplantation (HSCT) contributes to the control of leukemia. Our laboratory has demonstrated in a murine model that vaccination of recipients after transplantation with recipient tumor vaccines does not exacerbate graft-versus-host disease but does induce meaningful graft-versus-tumor effects. We previously demonstrated that part of the reason for the lack of graft-versus-host disease from post-transplantation vaccination is due to gradual acquisition of tolerance or unresponsiveness to recipient immunodominant minor histocompatibility antigens that are ubiquitously expressed in the recipient.

Down-regulation of antihost alloreactivity after bone marrow transplant permits relapse of hematological malignancy.

Relapse of leukemia remains a common event after allogeneic bone marrow transplantation, despite potential donor antihost alloreactivity present in most transplants. This work examined posttransplant relapse of the DBA/2 P815 mastocytoma in a murine model of MHC-matched, minor histocompatibility antigen (mHAg)-mismatched bone marrow transplantation (BALB/c donors into DBA/2 recipients). Antihost alloreactivity was associated with reduction of posttransplant tumor burden and prolongation of survival, but posttransplant relapse commonly occurred.