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Alopecia areata (AA) is a common autoimmune disease resulting from damage of the hair follicle by T cells. The immune pathways required for autoreactive T cell activation in AA are not defined limiting clinical development of rational targeted therapies (1). Genome-wide association studies (GWAS) (2) implicated ligands for the NKG2D receptor (product of the KLRK1 gene) in disease pathogenesis. Here, we show that cytotoxic [CD8.sup.+][NKG2D.sup.+] T cells are both necessary and sufficient for the induction of AA in mouse models of disease. Global transcriptional profiling of mouse and human AA skin revealed gene expression signatures indicative of cytotoxic T cell infiltration, an interferon-γ (IFN-γ) response and upregulation of several γ-chain (γc) cytokines known to promote the activation and survival of IFN-γ-producing [CD8.sup.+][NKG2D.sup.+] effector T cells. Therapeutically, antibody-mediated blockade of IFN-γ, interleukin-2 (IL-2) or interleukin-15 receptor β (IL-15Rb) prevented disease development, reducing the accumulation of [CD8.sup.+][NKG2D.sup.+] T cells in the skin and the dermal IFN response in a mouse model of AA. Systemically administered pharmacological inhibitors of Janus kinase (JAK) family protein tyrosine kinases, downstream effectors of the IFN-γ and [γ.sub.c] cytokine receptors, eliminated the IFN signature and prevented the development of AA, while topical administration promoted hair regrowth and reversed established disease. Notably, three patients treated with oral ruxolitinib, an inhibitor of JAK1 and JAK2, achieved near-complete hair regrowth within 5 months of treatment, suggesting the potential clinical utility of JAK inhibition in human AA., Alopecia areata is a T cell-mediated autoimmune disease characterized phenotypically by hair loss and, histologically, by infiltrating T cells surrounding the hair follicle bulb (reviewed in ref. 1). Previous studies [...]

We have developed a model of autoimmunity to investigate autoantibody-mediated cross-presentation of self antigen. RIP-mOVA mice, expressing OVA in pancreatic [beta] cells, develop severe autoimmune diabetes when given OT-I cells [...]

Plamotamab (XmAb SP ® sp 13676) is a humanized bsAb that binds both CD3 and the tumor antigen CD20 in order to recruit cytotoxic T cells to kill CD20+ tumor cells. As shown in Figure 2(C), the patient's right inner thigh EMWM tumor that completely disappeared after 2 cycles of XmAb SP ® sp 13676 had a dense CD8+ T cell infiltrate whereas the left anterolateral thigh EMWM tumor that grew in size after 2 cycles of XmAb SP ® sp 13676 had a scattered CD8+ T cell infiltrate (Figure 2(G)). (E) PET-CT images of left anterolateral thigh soft tissue tumor after two cycles of XmAb®13676.(F) PET-CT images of right inner thigh soft tissue tumors after four cycles of XmAb®13676. Patients having nonsense CXCR4 mutations have lower ORR to ibrutinib compared to frameshift mutations and wild type (55%, 79% and 85%, respectively; I p i = < 0-001) as well as lower PFS; 43 months vs. not reached for patients with frameshift mutations and wildtype CXCR4 mutations ( I p i = 0.01) [[7]]. [Extracted from the article]

Inhibitory receptors have been proposed to modulate the in vivo cytotoxic response against tumor targets for both spontaneous and antibody-dependent pathways. Using a variety of syngenic and xenograft models, we demonstrate here that the inhibitory Fc[gamma]RIIB molecule is a potent regulator of antibody-dependent cell-mediated cytotoxicity in vivo, modulating the activity of Fc[gamma]RIII on effector cells. Although many mechanisms have been proposed to account for the anti-tumor activities of therapeutic antibodies, including extended half-life, blockade of signaling pathways, activation of apoptosis and effector-cell-mediated cytotoxicity, we show here that engagement of Fc[gamma] receptors on effector cells is a dominant component of the in vivo activity of antibodies against tumors. Mouse monoclonal antibodies, as well as the humanized, clinically effective therapeutic agents trastuzumab (Herceptin[sup.[R]]) and rituximab (Rituxan[sup.[R]]), engaged both activation (Fc[gamma]RIII) and inhibitory (Fc[gamma]RIIB) antibody receptors on myeloid cells, thus modulating their cytotoxic potential. Mice deficient in Fc[gamma]RIIB showed much more antibody-dependent cell-mediated cytotoxicity; in contrast, mice deficient in activating Fc receptors as well as antibodies engineered to disrupt Fc binding to those receptors were unable to arrest tumor growth in vivo. These results demonstrate that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner Fc[gamma]RIIB., Author(s): Raphael A. Clynes [1]; Terri L. Towers [1]; Leonard G. Presta [2]; Jeffrey V. Ravetch (corresponding author) [1] Passive and active protection against pulmonary metastasis in the syngenic B16 [...]

The high-affinity receptor for IgG and the T cell receptor-CD3 complex are associated with the gamma subunit of immunoglobulin Fc receptors which lead to immunocompromised mice when target-disrupted. The macrophages from these mice show inability to phagocytose antibody-coated particles and exhibit defective NK cell-mediated antibody-dependent cytotoxicity and mast cell-mediated allergic response. However, T cell development in these mice is not compromised by the absence of the gamma chain.