Mingjian Fei

Genentech

Inhibiting MerTK on macrophages is a promising therapeutic strategy for augmenting anti-tumor immunity. However, blocking MerTK on retinal pigment epithelial cells (RPEs) results in retinal toxicity. Bispecific antibodies (bsAbs) containing an anti-MerTK therapeutic and anti-PD-L1 targeting arm were developed to reduce drug binding to MerTK on RPEs...

Here, we explore whether PEGylation of antibodies can modulate their biodistribution to the eye, an organ once thought to be immune privileged but has recently been shown to be accessible to IV-administered large molecules, such as antibodies. We chose to PEGylate an anti-MerTK antibody, a target with known potential for ocular toxicity, to minimiz...

While antibody-dependent cellular phagocytosis mediated by activating Fcγ receptor is a key mechanism underlying many antibody drugs, their full therapeutic activities can be restricted by the inhibitory Fcγ receptor IIB (FcγRIIB). Here, we describe a bispecific antibody approach that harnesses phagocytic receptor CLEC5A (C-type Lectin Domain Conta...

Clearance of apoptotic cells by macrophages prevents excessive inflammation and supports immune tolerance. Here, we examined the effect of blocking apoptotic cell clearance on anti-tumor immune response. We generated an antibody that selectively inhibited efferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulation of apop...

The expansion of CD8 ⁺ CD28 – T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8 ⁺ CD28 – T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regula...

Figure 2. SIRT1 interacts with RORt. (A) Flag-tagged WT or H363Y mutant SIRT1 was immunoprecipitated from transfected 293T cells and probed as indicated. (B) RORt was immunoprecipitated from thymocytes and Th17 cells, and probed with antibody against SIRT1. (C) Immuno-precipitation using lysates of 293T cells co-transfected with constructs encodi...

Figure 2. SIRT1 interacts with RORt. (A) Flag-tagged WT or H363Y mutant SIRT1 was immunoprecipitated from transfected 293T cells and probed as indicated. (B) RORt was immunoprecipitated from thymocytes and Th17 cells, and probed with antibody against SIRT1. (C) Immuno-precipitation using lysates of 293T cells co-transfected with constructs encodi...

The balance of effector and regulatory T cell function, dependent on multiple signals and epigenetic regulators, is critical to immune self-tolerance. Dysregulation of T helper 17 (Th17) effector cells is associated with multiple autoimmune diseases, including multiple sclerosis. Here, we report that Sirtuin 1 (SIRT1), a protein deacetylase previou...

Oxidative stress has been implicated in both normal aging and various neurodegenerative disorders and it may be a major cause of neuronal death. Chaperone-mediated autophagy (CMA) targets selective cytoplasmic proteins for degradation by lysosomes and protects neurons against various extracellular stimuli including oxidative stress. MEF2A (myocyte...

Dendritic cell (DC)-T cell interactions that underlie inducible/adaptive regulatory T cell generation and airway tolerance are not well understood. In this study, we show that mice lacking CD11c(hi) lung DCs, but containing plasmacytoid DCs (pDCs), fail tolerization with inhaled Ag and cannot support Foxp3 induction in vivo in naive CD4(+) T cells....

Although Sirtuin 1 (SIRT1), an NAD-dependent protein deacetylase, has emerged as a critical regulator of the cell cycle, replicative senescence, inflammation, and metabolism, its contribution to immune function remains to be fully investigated. Here we report that SIRT1 regulates the function of IL-17 producing CD4 T helper cells (Th17 cells) by mo...

Aspergillus fumigatus (A. fumigatus) is commonly associated with allergic bronchopulmonary aspergillosis (ABPA), which represents one of the most extreme manifestations of fungal allergy. Eosinophils are considered to be effector cells mediating lung dysfunction, but there is increasing appreciation that pulmonary neutrophilia also contributes to A...

Aspergillus fumigatus is associated with allergic bronchopulmonary aspergillosis, a pulmonary allergic disorder, in which neutrophilia predicts a poor outcome. In our efforts to recapitulate fungus-induced airway neutrophilia in the allergic setting, we found that similar exposure to the fungus resulted in a neutrophil-dominated response in BALB/c...

Foxp3+ Regulatory T cells (Treg), both naturally occurring thymus-derived nTregs and peripherally induced Foxp3+ induced Tregs (iTreg), play a critical role in suppressing immune responses to self as well as external antigens, ensuring protection from autoimmune and allergic diseases such as asthma. Recent investigations have established a role for...

Aspergillus fumigatus is commonly associated with allergic bronchopulmonary aspergillosis in patients with severe asthma in which chronic airway neutrophilia predicts a poor outcome. We were able to recapitulate fungus-induced neutrophilic airway inflammation in a mouse model in our efforts to understand the underlying mechanisms. However, neutroph...

Kinetics of gene expression in the lungs of Aspergillus-infected mice. (A) Mice were infected with various doses of RC or given PBS intratracheally and lungs were harvested after 48 hours of infection for total RNA extraction. Quantitative RT-PCR was performed to measure mRNA expression corresponding to various AAM markers. (B) Mice were infected w...

The ubiquitous fungus Aspergillus fumigatus is associated with chronic diseases such as invasive pulmonary aspergillosis in immunosuppressed patients and allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis or severe asthma. Because of constant exposure to this fungus, it is critical for the host to exercise an immediate...

Macrophages adopt an ‘alternative phenotype’ in a Th2-mediated inflammatory environment. Although identified in a wide variety of disease conditions, alternatively activated macrophages (AAMs) have been functionally best studied in helminth infections. The heterogeneity of functions performed by AAMs is attributed to the diverse molecules they expr...

Aspergillus fumigatus is a fungus that induces allergic bronchopulmonary aspergillosis (ABPA), a disease exhibiting both airway eosinophilia and neutrophilia. The disease is acquired through the inhalation of spores, which are cleared efficiently in healthy humans but not in patients with cystic fibrosis or asthma. The impaired clearance and sustai...

Dendritic cells are integral in instructing the differentiation of T helper cells into Th1, Th2 and Th17 subsets and IL-6 is a key regulator of CD4 T cell differentiation .In this study, we investigated pathways in DCs that promote IL-6 production. We show exposure of DCs to house dust mite (HDM) or the mucosal adjuvant cholera toxin (CT) promotes...

Indoleamine 2,3 dioxygenase (IDO) has emerged as an important mediator of immune tolerance via inhibition of Th1 responses. However, the role of IDO in antigen-induced tolerance or allergic inflammation in the airways that is regulated by Th2 responses has not been elucidated. By using IDO−/− mice, we found no impairment of airway tolerance, but, s...

Dendritic cells (DCs) are integral to the differentiation of T helper cells into T helper type 1 T(H)1, T(H)2 and T(H)17 subsets. Interleukin-6 (IL-6) plays an important part in regulating these three arms of the immune response by limiting the T(H)1 response and promoting the T(H)2 and T(H)17 responses. In this study, we investigated pathways in D...

Emerging evidence supports the concept that T helper type 17 (T(H)17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the T(H)17 lineage, and both were crucial for maintaining local control of the Gram-negative...

Asthma is an inflammatory disease of the small airways caused by an exaggerated CD4 Th2 response. We have shown that OVA coupled with cholera toxin (CT) when administered intranasally into mice recapitulate the hallmarks of asthma. In vitro, CT ‐treated Dcs prime naïve T cells towards a Th2 response. We undertook a microarray approach to dissect th...

Aspergillus fumigatus (A. fumigatus) is a fungus that induces allergic airways diseases in immunocompromised patients, and in patients with cystic fibrosis or severe asthma. Host defense against this fungus depends on both innate and adaptive immunity. DCs have been shown to transport conidia or hyphae from the airway to the lung draining lymph nod...

IL-10 is known as a negative regulator for inflammatory diseases, including contact dermatitis. However, only a few drug candidates are reported to induce endogenous IL-10. We sought to elucidate a new mechanism underlying the immunosuppressive properties of astilbin through negative cytokine regulation in comparison with the effective pattern with...

In the present paper, the effect of Fumigaclavine C, a fungal metabolite, on experimental colitis was examined. Fumigaclavine C, when administered intraperitoneally once a day, significantly reduced the weight loss and mortality rate of mice with experimental colitis induced by intrarectally injection of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)...

Two novel metal-organic frameworks with different structures were obtained by reactions of Pbl(2) with N,N'-bis(3-pyridylmethyl)-1,4-biphenylenedimethyleneimine (L) under different M/L ratios. When the M/L ratio is 1:1, L bridges [Pbl(2)](n) chains to form a layered organic-inorganic hybrid compound with the empirical formula [Pb(L)I-2] (1). When c...