NIH grant: Injectable acellular hydrogels for local immunoregulation and tolerance (1R21AI199487-01)

retained text

NIH grant 1R21AI199487-01: Injectable acellular hydrogels for local immunoregulation and tolerance
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Christopher B Rodell. Award: $222786.
Start: 2026-06-24T00:00:00.
PROJECT SUMMARY
Autoimmune diseases afflict more than 15 million Americans, one-third of which have two or more autoimmune
conditions. An elevated abundance of pro-inflammatory and/or autoreactive T cells (Teff) and reduced levels of
regulatory T cells (Tregs) underlies disease onset, progression, and the common relapsing-and-remitting nature
of symptoms. Medical management of autoimmune conditions focuses on systemic immunosuppression;
though, it is a suboptimal solution that i) addressed symptoms but is not curative and ii) precipitates risk of
opportunistic infection and tumorigenesis. Hence, there is an urgent need to re-establish homeostatic Teff/Tregs
function in order to regulate chronic inflammation and reinstate antigen-specific self-tolerance – which would be
a Holy Grail for autoimmune therapies. There remains, however, no safe and effective therapy to procure and
maintain Tregs. Treg-directed therapies have focused primarily on in vivo Treg induction via delivery of soluble
factors or adoptive cell transfer, but these techniques are limited by 1) impurities of autoreactive and pro-
inflammatory T cells, 2) phenotypic instability of induced Tregs, 3) challenges in controlled drug delivery, and 4)
off-target effects. These drawbacks have motivated us to develop an injectable granular hydrogel that induces T
regs and complements their cellular memory through co-inhibitory signaling. The hydrogel enables the localized
presentation of an onco-fetal immune checkpoint, B7x, covalently tethered through azide-alkyne click chemistry.
Functionally, B7x both inhibits Teff differentiation and function as well as induces Tregs and bolsters their function.
Our preliminary data demonstrate that C-terminal azide modification of B7x does not detrimentally affect it’s
ability to induce Tregs. Subcutaneous injection of B7x-conjugated hydrogels in mice increased local Treg
abundance and mitigated psoriasis in pilot studies. We hypothesize that the B7x-conjugated granular hydrogels
will alleviate local inflammation by expanding Treg populations thereby creating an immunoregulatory niche that,
when coupled with the delivery of disease-specific self-antigens, will foster tolerance and mitigate the
autoimmune response. This hypothesis will be examined through two aims. In the imiquimod-induced psoriasis
model, we will first determine if B7x-conjugated hydrogels induce Tregs and mitigate Teff response through
immunoregulatory mechanisms. In the second aim, we will examine if the co-delivery of disease-specific antigens
within this immunoregulatory niche will foster tolerance and mitigate disease severity in a murine model of
experimental autoimmune encephalomyelitis (EAE). Our approach toward Treg induction and maintenance
represents a novel and translatable approach, as the hydrogels will be delivered by minimally invasive injection.
Moreover, modularity of the material platform allows for facile bioconjugation of additional immunoregulatory
signals as well as the co-delivery of antigen of choice. It therefore holds broad potential for treating autoimmune
dysfunctions, organ rejection, and chronic inflammation after tissue injury.

document fetched 2026-07-05 08:57