Humanized Mice as a Model for Aberrant Responses in Human T Cell Immunotherapy

Abstract

Immune deficient mice, reconstituted with human stem cells, have been used to analyze human immune responses in vivo. Although they have been used to study immune responses to xenografts, allografts, and pathogens, there have not been models of autoimmune disease in which the mechanisms of the pathologic process can be analyzed. We have found that reconstituted “humanized” mice treated with anti-CTLA-4 antibody (ipilimumab) develop autoimmune disease characterized by hepatitis, adrenalitis, sialitis, ANAs, and weight loss. Induction of autoimmunity involved activation of T cells and cytokine production and increased infiltration of antigen presenting cells. When anti-CTLA-4 mAb treated mice were co-treated with anti-CD3 mAb (teplizumab) hepatitis and ANAs were no longer seen and weight loss did not occur. The anti-CD3 blocked proliferation and activation of T cells, release of IFNγ and TNF, macrophage infiltration and release of IP-10 that was induced with anti-CTLA-4 mAb. We also found increased levels of Tregs (CD25+CD127-) in the spleen and mesenteric lymph nodes in the mice treated with both antibodies and greater constitutive phosphorylation of STAT5 in Tregs in spleen cells compared to mice treated with anti-CTLA-4 mAb alone. We describe the first model of human autoimmune disease in vivo. Humanized mice may be useful for understanding the mechanisms of biologics that are used in patients. Hepatitis, lymphadenopathy, and other inflammatory sequelae are side effects of ipilumimab treatment in humans and the present study may provide insights into this pathogenesis and the effects of immunologics on autoimmunity.

Endocrine dysfunctions during treatment of immune-checkpoint inhibitors

“…In animal models, anti-CTLA-4-antibodies were reported to induce thyroiditis [48] , adrenalitis [49] , and T1DM [50] . Anti-PD-1 antibodies blocks PD-1 pathway which suppress autoimmunity.…”

Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3

“…Similar to the phenotype in our IPEX(DR1) mice, a recent report also demonstrated a role for human Tregs in immune homeostasis in humanized mice by showing that administration of antibodies blocking CTLA-4, a molecule critical for Treg suppressive function, 50-52 also caused weight loss, liver inflammation, and antinuclear antibodies. 53 One possibility for the multiorgan inflammation is that the IPEX mice developed allogeneic graft versus host disease (GVHD) because the IPEX donor was not matched for the DR1*01:01 allele; a previous report using NSGAb°mice expressing human DR4 injected with human peripheral blood mononuclear cells resulted in allogeneic GVHD. 54 However, human stem cell reconstitution in 1-day-old NSGAb°DR1-neonates gives rise to human T cells selected on murine (and likely human) antigens in the mouse thymus, where autoreactive T cells are likely deleted.…”

“…The model described here exhibits enhanced adaptive immune function, which circumvents the requirement of surgically implanted autologous thymic and liver tissue and enables use of HSCs from genetically defined patients. 53,55 These mice will likely be most useful for studies pertaining to T-cell responses and immune-mediated diseases resulting from Treg dysfunction and/or aberrant effector CD4…”

Microbiota control immune regulation in humanized mice

“…Our findings highlight the critical role of the microbiota in this setting since teplizumab restored tolerance when autoimmunity was induced by other means (i.e., anti-CTLA-4 mAb) (30). These observations may have broad application to understanding the basis for autoimmune diseases and the increased frequency of these ailments that have been associated with the avoidance of infections and use of antibiotics in Western countries (43).…”

“…There was spontaneous development of autoantibodies (ANAs), and increased levels of IFN-γ in the circulation with activation of cells in the gut wall. Previously we found that teplizumab treatment prevented xenogeneic skin graft rejection in humanized mice by inducing T cells with regulatory function (17,30), which we now show is modified by antibiotic treatment. The tolerogenic response to teplizumab requires migration to the gut and activation of cells at that location but the antibiotic treatment did not affect cell migration.…”