Biology subjects

Lauterbach, A. L.

Publications and source records attributed to Lauterbach, A. L..

3 recordsLinked to original sources

bioRxiv2026

Serum albumin-fused interleukin-10 prevents neuroinflammation by promoting immunoregulation in the secondary lymphoid organs and limiting immune cell infiltration in the spinal cord

Interleukin-10 (IL-10) is a potent immunoregulatory cytokine that suppresses pro-inflammatory cytokine production, reduces antigen presentation by myeloid cells, promotes M2 macrophage polarization, and inhibits T cell activation. Despite these well-established immunoregulatory functions, efforts to harness recombinant IL-10 therapeutically have been limited by its short plasma half-life and poor retention in the secondary lymphoid organs (SLOs), key sites of autoreactive T cell priming in autoimmune disease. Previously, we engineered a fusion of serum albumin and IL-10 (SA-IL-10) with extended half-life and enhanced exposure in the SLOs following intravenous administration. Here, we integrate human transcriptomic analyses and a murine model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE), to investigate how sustained IL-10 exposure in the SLOs modulates immune responses under inflammatory conditions. Human single-cell RNA sequencing analyses revealed reduced IL-10 expression alongside increased IL-10 receptor expression across multiple immune cell populations in treatment-naive patients with multiple sclerosis (MS), motivating the investigation of IL-10-based immunomodulatory strategies. Prophylactic SA-IL-10 administration prevented the development and progression of EAE with superior efficacy to wild type IL-10 and comparable protection to fingolimod, an FDA-approved MS therapy. Immunophenotyping of the SLOs revealed that SA-IL-10 suppressed pathogenic, antigen-specific ROR{gamma}t+ Foxp3- TH17 T cells, CD86+ M1-like macrophages, CD86+ dendritic cells, and pro-inflammatory cytokine production, while expanding immunoregulatory CD206+ M2-like macrophages and increasing the frequency of multiple checkpoint markers (CTLA-4, PD-1, TIGIT, ICOS) on GATA3+ Foxp3- TH2 cells. Despite the absence of direct central nervous system targeting, SA-IL-10 treatment also reduced the infiltration of macrophages, dendritic cells, and CD4+ T cells into the spinal cord. Repeated SA-IL-10 administration was well tolerated, as treated EAE mice gained significantly more body weight over the course of treatment compared to PBS- and WT IL-10-treated controls, and exhibited plasma biochemistry parameters comparable to control animals at study endpoint. Together, these findings demonstrate that increasing IL-10 exposure in the SLOs suppresses neuroinflammation by promoting immunoregulation.

immunology↗

bioRxiv2024

Engineered Flt3L Drives Tolerogenic State to Attenuate Anti-drug Antibody Responses

Immune reactions to protein drugs present substantial challenges to protein replacement for treating congenital diseases and metabolic deficiencies, due to the lack of endogenous tolerance or the protein drugs partial or total non-human origin. We sought to transiently modify the immune environment when the adaptive response to the drug antigen is mounted to lessen future reactions upon continued therapeutic treatment, without modifying the drug itself. Herein, we characterize a recombinant fusion of the cytokine Flt3L to serum albumin and describe a novel pathway of Flt3L-mediated immune regulation. We highlight reduced activation of dendritic cells (DC) as well as an increased frequency of DCs expressing LAP, a TGF-{beta} precursor. These effects in combination with low doses of the exogenous antigen led to less TH2 differentiation. This enabled a tolerance-biasing induction regimen to significantly decrease anti-drug antibodies upon repeated exposure to a clinically used, immunogenic fungal enzyme, rasburicase. This induction regimen reduced the Tfh compartment and increased Tfh cells expressing Foxp3 and PD-L1, suggesting a regulatory response. Overall, we introduce the use of a Flt3L variant as an induction therapeutic to modulate the innate immune response, thereby attenuating the adaptive reaction to antigenic protein drugs and addressing an unmet clinical need.

bioengineering↗

bioRxiv2023

Synthetically mannosylated antigens induce antigen-specific humoral tolerance and reduce anti-drug antibody responses to immunogenic biologics

Immunogenic biologics trigger an anti-drug antibody (ADA) response in patients, which reduces efficacy and increases adverse reactions. Our laboratory has previously shown that targeting protein antigen to the liver microenvironment can reduce antigen-specific T cell responses; herein, we present a strategy to increase delivery of otherwise immunogenic biologics to the liver via conjugation to a synthetic mannose polymer (p(Man)). This delivery leads to reduced antigen-specific T follicular helper cell and B cell responses resulting in diminished ADA production, which is maintained throughout subsequent administrations of the native biologic. We found that p(Man)-antigen treatment impairs the ADA response against recombinant uricase, a highly immunogenic biologic, without a dependence on hapten immunodominance or control by Tregs. We identify increased TCR signaling and increased apoptosis and exhaustion in T cells as effects of p(Man)-antigen treatment via transcriptomic analyses. This modular platform may enhance tolerance to biologics, enabling long-term solutions for an ever-increasing healthcare problem.

bioengineering↗