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. 2023 Dec;53(12):e2350454.
doi: 10.1002/eji.202350454. Epub 2023 Aug 31.

A human immune system (HIS) mouse model that dissociates roles for mouse and human FcR+ cells during antibody-mediated immune responses

Anna Louisa Thaller  1 , Friederike Jönsson  2 , Oriane Fiquet  1 , Solenne Marie  1 , Jean-Marc Doisne  1 , Giulia Girelli-Zubani  1 , Toshiki Eri  1 , Priyanka Fernandes  1 , Evgeny Tatirovsky  1 , Francina Langa-Vives  3 , Pierre Bruhns  2 , Hélène Strick-Marchand #  1 , James P Di Santo #  1
Affiliations
Free article

A human immune system (HIS) mouse model that dissociates roles for mouse and human FcR+ cells during antibody-mediated immune responses

Anna Louisa Thaller et al. Eur J Immunol. 2023 Dec.
Free article

Abstract

Human immune system (HIS) mice provide a model to study human immune responses in vivo. Currently available HIS mouse models may harbor mouse Fc Receptor (FcR)-expressing cells that exert potent effector functions following administration of human Ig. Previous studies showed that the ablation of the murine FcR gamma chain (FcR-γ) results in loss of antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vivo. We created a new FcR-γ-deficient HIS mouse model to compare host (mouse) versus graft (human) effects underlying antibody-mediated immune responses in vivo. FcR-γ-deficient HIS recipients lack expression and function of mouse activating FcRs and can be stably and robustly reconstituted with human immune cells. By screening blood B-cell depletion by rituximab Ig variants, we found that human FcγRs-mediated IgG1 effects, whereas mouse activating FcγRs were dominant in IgG4 effects. Complement played a role as an IgG1 variant (IgG1 K322A) lacking complement binding activity was largely ineffective. Finally, we provide evidence that FcγRIIIA on human NK cells could mediate complement-independent B-cell depletion by IgG1 K322A. We anticipate that our FcR-γ-deficient HIS model will help clarify mechanisms of action of exogenous administered human antibodies in vivo.

Keywords: ADCC; Antibody-mediated immune responses; Fc receptors; Human immune system (HIS) mice; NK cells.

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