Suppression of anti-drug antibody formation against coagulation factor VIII by oral delivery of anti-CD3 monoclonal antibody in hemophilia A mice

Bertolini, Thais; Herzog, Roland W.; Kumar, Sandeep; Sherman, Alexandra; Rana, Jyoti; Kaczmarek, Radosław; Yamada, Kentaro; Arisa, Sreevani; Lillicrap, David; Terhorst, Cox; Daniell, Henry; Biswas, Moanaro

doi:10.1016/j.cellimm.2023.104675

Cited by 5 publications

(4 citation statements)

References 82 publications

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“…In contrast, FoxP3 + LAP + dual positive cells represent an activated form of traditional FoxP3 + Treg (rather than a distinct subset) that acquired those gene expression characteristics of FoxP3 -LAP + cells that relate to TGF-b and ICOS expression. Both these suppressive cell types expressed surface LAP, supporting prior claims in the literature that TGFb complexed to LAP is sufficient to induce FoxP3 expression in a contact dependent manner (12,13,33,(58)(59)(60)(61).…”

Section: Lap + Foxp3and Foxp3 + Treg Have Distinct Gene Expression Pa...supporting

confidence: 79%

“…We compared T conv (FoxP3 -LAP -), FoxP3 + LAP -, FoxP3 + LAP + , FoxP3 -LAP + cells (n=4/group). The FoxP3 + LAP + population highly upregulated activation and co-inhibitory molecules such as CD69, CD44, CTLA-4, PD1, LAG3, ICOS, GARP, and NRP1, consistent with its role as an activated cell subset with superior suppressive function (12,33) (Figure 4A). This population also upregulated the transcription factors IRF4 and BATF, which initiates differentiation towards an effector Treg phenotype (51).…”

Section: Foxp3 + Lapand Foxp3 -Lap + Cells Exhibit Distinct Gene Sign...mentioning

confidence: 73%

“…Recently, we demonstrated that a short course of low dose oral anti-CD3 monoclonal antibody was effective in inhibiting ADA responses to FVIII. Suppression was accompanied by early induction of FoxP3 + LAP, FoxP3 -LAP + , and FoxP3 + LAP + populations of CD4 + T cells in the spleen and MLN (33). Therefore, we have shown in multiple studies and via different treatment strategies that oral tolerance is established by a heterogenous population of T cells with a regulatory phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Distinct functions and transcriptional signatures in orally induced regulatory T cell populations

Biswas,

So,

Bertolini

et al. 2023

Front. Immunol.

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Oral administration of antigen induces regulatory T cells (Treg) that can not only control local immune responses in the small intestine, but also traffic to the central immune system to deliver systemic suppression. Employing murine models of the inherited bleeding disorder hemophilia, we find that oral antigen administration induces three CD4+ Treg subsets, namely FoxP3+LAP-, FoxP3+LAP+, and FoxP3-LAP+. These T cells act in concert to suppress systemic antibody production induced by therapeutic protein administration. Whilst both FoxP3+LAP+ and FoxP3-LAP+ CD4+ T cells express membrane-bound TGF-β (latency associated peptide, LAP), phenotypic, functional, and single cell transcriptomic analyses reveal distinct characteristics in the two subsets. As judged by an increase in IL-2Rα and TCR signaling, elevated expression of co-inhibitory receptor molecules and upregulation of the TGFβ and IL-10 signaling pathways, FoxP3+LAP+ cells are an activated form of FoxP3+LAP- Treg. Whereas FoxP3-LAP+ cells express low levels of genes involved in TCR signaling or co-stimulation, engagement of the AP-1 complex members Jun/Fos and Atf3 is most prominent, consistent with potent IL-10 production. Single cell transcriptomic analysis further reveals that engagement of the Jun/Fos transcription factors is requisite for mediating TGFβ expression. This can occur via an Il2ra dependent or independent process in FoxP3+LAP+ or FoxP3-LAP+ cells respectively. Surprisingly, both FoxP3+LAP+ and FoxP3-LAP+ cells potently suppress and induce FoxP3 expression in CD4+ conventional T cells. In this process, FoxP3-LAP+ cells may themselves convert to FoxP3+ Treg. We conclude that orally induced suppression is dependent on multiple regulatory cell types with complementary and interconnected roles.

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Section: Lap + Foxp3and Foxp3 + Treg Have Distinct Gene Expression Pa...supporting

confidence: 79%

Section: Foxp3 + Lapand Foxp3 -Lap + Cells Exhibit Distinct Gene Sign...mentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

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Distinct functions and transcriptional signatures in orally induced regulatory T cell populations

Biswas,

So,

Bertolini

et al. 2023

Front. Immunol.

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“…An alternative approach to mitigating anti-FVIII antibodies involves oral delivery of anti-CD3 monoclonal antibody. 73 This method has the potential to modulate systemic immune responses, resulting in a reduction of anti-FVIII antibody titers, all without the need for T cell depletion. Further enhancements are anticipated, especially regarding the establishment of FVIII tolerance.…”

Section: Discussionmentioning

confidence: 99%