Reprogramming Innate & Adaptive Immunity for Durable Islet Allograft Survival- Dr. Haval Shirwan PhD
On Demand video from the May 12 2026 talk
🎬 ON DEMAND VIDEO
Reprogramming Innate & Adaptive Immunity for Durable Islet Allograft Survival Dr. Haval Shirwan PhD | University of Missouri | 2026
💬 Key Quote
“The initial decision the immune system makes is critical — what we need to do is trigger a mechanism that takes the immune system toward the regulatory path. You don’t need to maintain FasL for a long term to trigger that regulatory response.” — Dr. Haval Shirwan, PhD
🔬 Foundational Insights as They Apply to T1D
Every islet transplant confronts two sequential immunological crises that unfold on entirely different timescales — and that have, until now, been addressed as if they were separate problems. The first strikes within minutes to hours: instant blood-mediated inflammatory reaction (IBMIR), triggered by islets entering the bloodstream or a new tissue environment. Tissue factor expression by islets activates coagulation; danger-associated molecular patterns recruit innate immune cells; complement is activated. By some estimates, more than 50% of the transplanted islet mass is destroyed within the first 24 hours by this innate immune storm alone — before a single adaptive T cell has even recognized a donor antigen. The second crisis unfolds over weeks to months: alloreactive T cells — primed by antigen-presenting cells in the graft draining lymph nodes, expanded by IL-2, and differentiated into effector and memory populations — return to the graft and destroy the beta cells that survived the first wave. Current immunosuppressive regimens blunt both responses systemically, at the cost of serious toxicity, infection risk, and ultimately insufficient long-term protection.
Dr. Haval Shirwan’s Protex platform attacks both crises simultaneously, but from the graft outward rather than from the systemic immune compartment inward. The core insight is architectural: instead of flooding the body with immunosuppression to protect the graft, engineer the graft surface itself to display immunomodulatory molecules that locally redirect the immune response exactly where and when it is needed. The platform uses chimeric streptavidin fusion proteins — exploiting the near-covalent biotin–streptavidin interaction (Kd ~10⁻¹⁵ M) to anchor the extracellular domain of immune ligands to biotinylated cell or biomaterial surfaces with precision, reversibility, and dose control. No gene transfer. No viral vectors. No permanent genomic modification. Just a 15-minute biotinylation step, a wash, and incubation with the engineered protein — and the surface of the islet becomes an active participant in its own immune protection.
The most advanced molecule in this toolkit is FasL — the Fas ligand. FasL engages Fas (CD95) on the surface of activated T cells to trigger apoptosis. In normal immune homeostasis, this pathway is essential: humans lacking Fas or FasL develop autoimmune lymphoproliferative syndrome, with unchecked autoimmunity and no compensatory mechanism to substitute. In transplantation, the pathway is equally important: effector T cells that have encountered antigen upregulate Fas, making them selectively vulnerable to FasL-mediated elimination. T regulatory cells, by contrast, are relatively resistant to FasL-mediated killing — and in fact use FasL themselves as a mechanism to eliminate pathogenic T cells. Displaying FasL on the islet surface therefore creates a graft that eliminates its attackers while preserving its protectors — and, crucially, the apoptotic bodies generated in this process are taken up by phagocytes that shift to a TGF-β–secreting regulatory phenotype, amplifying the tolerogenic signal in a self-sustaining second wave.
🎯 Core Premise
The Protex platform positions immunomodulatory ligands — most critically FasL — on the surface of islets or FasL-displaying PEG microgels co-delivered with islets, creating a localized immune editing environment that eliminates alloreactive T cells at the graft site while generating a phagocyte-driven, TGF-β–dependent regulatory response that sustains long-term graft survival. On the innate side, co-engineering islets with CD47 (a “don’t eat me” signal that blocks phagocyte-mediated destruction) and thrombomodulin (which shifts thrombin activity from procoagulant toward anticoagulant and cytoprotective activated protein C) addresses IBMIR — dramatically improving engraftment in intraportal minimal mass models and reducing early innate immune destruction. Together, these two arms of the strategy address both the acute innate crisis and the chronic adaptive crisis, each from the graft surface outward, without systemic immunosuppression as the primary mechanism of protection.
🌟 Why This Talk Matters to T1D Scientists and Clinicians
For scientists: The mechanistic dissection of Protex-FasL tolerance is unusually rigorous for a translational immunology program. Dr. Shirwan’s lab established not only that FasL-engineered islets or microgels achieve long-term allograft survival in mice and non-human primates, but exactly how — using clodronate depletion of phagocytes to show that apoptotic body uptake is required, TGF-β blockade to confirm the downstream regulatory cytokine, T regulatory cell depletion at both induction and maintenance phases to show that Tregs are necessary for sustained survival, and adoptive retransplantation experiments to demonstrate that tolerance is graft-site-localized rather than systemic. The OVA–OT-II tracking system showing that alloreactive T cell proliferation is suppressed in the kidney draining lymph node but not systemically adds a spatial precision to the immunological picture that is rarely achieved in transplantation tolerance studies. Each mechanistic layer directly informs what the clinical product needs to do — and the iTolerance microgel platform is the manufacturable instantiation of that mechanism.
For clinicians: The translational path here is credible and specific. The 4/4 non-human primate data — intraomental FasL-microgel + islet co-transplants, rapamycin tapered and stopped at day 90, with documented insulin independence in at least one animal and sustained normoglycemia in all four through 130–180 days — represent a genuinely compelling large-animal dataset. The clinical target is the omentum, consistent with the NHP work and with the broader field’s interest in retrievable extrahepatic sites. The rapamycin induction regimen used in NHPs (trough ~30 ng/mL induction, ~4 ng/mL maintenance, stopped at day 90) raises a real clinical translation question — high induction levels are associated with toxicity in human islet recipients — but the goal of the clinical program is not to reproduce the NHP regimen exactly, but to test whether the tolerogenic mechanism is sufficient to allow immunosuppression minimization in humans. Phase 1 planning is underway, targeting late 2027.
3️⃣ Big Takeaways
1. FasL on the graft surface converts an immune attack into a self-amplifying tolerogenic circuit — and the mechanism has been dissected layer by layer. When alloreactive T cells infiltrate a FasL-displaying islet graft, they engage Fas on their own surface and undergo apoptosis. This is not merely passive elimination. The apoptotic bodies are phagocytosed by macrophages and dendritic cells at the graft site, which shift to a TGF-β–secreting immunoregulatory phenotype — generating a second wave of tolerance that expands and maintains graft-resident T regulatory cells. Block phagocyte activity with clodronate, and tolerance fails. Block TGF-β, and tolerance fails. Deplete T regulatory cells at induction or during maintenance, and tolerance fails. Each intervention maps to a defined step in the circuit. The localized nature of the response — normal mixed lymphocyte reactions to donor antigen persist systemically in long-term survivors — means the graft is protected without broad systemic immunosuppression. This mechanistic specificity is what makes the clinical program credible: the product is designed to trigger a defined tolerogenic pathway, not to hope that non-specific immunosuppression spares the graft.
2. Non-human primate data show 4/4 sustained graft survival with a transient, stoppable rapamycin regimen — a result that does not exist elsewhere in the allotransplantation field for islets without chronic immunosuppression. Four streptozotocin-diabetic cynomolgus macaques received intraomental co-transplants of allogeneic islets with FasL-displaying PEG microgels (1:2 islet-to-microgel ratio). Rapamycin was started at day -3, maintained at induction levels through approximately day 30, tapered to ~4 ng/mL maintenance through day 90, then stopped entirely. All four animals maintained graft function through the study endpoint (130–180 days; COVID prevented longer follow-up). Exogenous insulin requirements fell substantially in all animals; one animal required no exogenous insulin at endpoint. Glucose tolerance tests confirmed functional islet mass in long-term survivors. All controls rejected acutely within ~40 days. Critically, CD4+ effector memory, central memory, and stem-like memory T cells in both NHPs and humans constitutively express Fas — meaning the translational target cell population is present and susceptible in human recipients.
3. The off-the-shelf microgel format — FasL displayed on PEG particles rather than directly on islets — solves the manufacturing problem without sacrificing mechanism, and positions the technology for a first-in-human trial. The direct islet biotinylation and FasL-loading approach that established proof of concept requires engineering each donor preparation fresh at the time of transplantation — a practical limitation for clinical scale. The iTolerance-100 product instead pre-loads FasL onto biotin-functionalized PEG microgels (approximately islet-sized, ~150 μm) that can be manufactured under GMP, characterized, and co-delivered with islets at a defined ratio. Andreas García’s lab at Georgia Tech established that these FasL-microgels induce apoptosis in Fas-expressing cells in vitro and reproduce the in vivo tolerogenic outcome in rodent models. A critical mechanistic control — chemically conjugating FasL to the microgel surface rather than displaying it positionally through streptavidin — abolished apoptotic activity, confirming that the Protex positional display architecture is not merely convenient but mechanistically essential. GMP manufacturing of the chimeric FasL-streptavidin protein (expressed in insect cells) is now complete; a phase 1 IND is being pursued with a target of late 2027.
❓ Key Questions from the Discussion
Will free or shed FasL trigger hepatocyte apoptosis during portal transit — and has the FDA pressed on this? Dr. Shirwan clarified that the iTolerance-100 product is delivered to the omentum, not infused into the portal vein — meaning the liver is not in the direct path of FasL exposure. Systemic FasL is detectable in NHP serum post-transplant, but hepatocytes are classified as Fas type II cells, in which apoptosis requires pro-inflammatory co-signals not present under these conditions. No liver enzyme elevation was seen in rodents or NHPs. Dr. Shirwan also noted that the Fas pathway is required for liver regeneration itself, contextualizing why therapeutic FasL exposure at physiological levels does not translate to hepatotoxicity. The hepatotoxicity question has been raised in FDA discussions, and the NHP safety data constitute the primary evidence supporting the IND.
What delayed the phase 1 IND — and is the rapamycin induction level a clinical translation barrier? GMP manufacturing of the chimeric FasL-streptavidin protein expressed in insect cells was the primary bottleneck, requiring a contracted manufacturing organization, novel characterization assays, and an extensive preclinical package. Additional FDA-requested studies are now complete. Separately, Dr. Herring raised the clinical concern that the NHP induction rapamycin trough level (~30 ng/mL) would be poorly tolerated in humans — mouth ulcers and other complications are limiting even at 5–10 ng/mL in islet recipients. Dr. Shirwan acknowledged this, noting that NHP rapamycin absorption is substantially lower than in humans, so the actual NHP exposure may correspond to a lower human-equivalent dose, and that the maintenance level (~4 ng/mL through day 90, then stopped) is within current clinical norms. The phase 1 design will need to address this directly.
Is the omentum a viable clinical transplant site given that early human intraomental trials produced durable function in only 1–2 of ~10 patients?Dr. Bernard Herring raised this directly, noting that the omentum is anatomically variable — thin and avascular in some patients, well-vascularized in others — and that the immunosuppressive regimens used in early human intraomental programs may not be comparable to what Protex is targeting. Dr. Shirwan acknowledged the site’s clinical track record while noting that NHP data at the omentum remain encouraging, that the benign immunomodulatory approach of Protex differs fundamentally from prior programs, and that alternative sites — including the rectus abdominis sheath approach pioneered by Deng’s group in China — are being evaluated experimentally. A direct collaboration with Deng’s group was raised as a possibility.
How long does FasL persist on the microgel surface in vivo — and is transient expression sufficient to induce durable tolerance? FasL half-life on engineered surfaces in rodents is approximately 3.5 days; in NHPs, FasL was detectable through day 12 post-transplant and minimal thereafter. Dr. Shirwan’s view is that this window is precisely the immunologically critical one: T cells make their activation and differentiation decisions within minutes to hours of antigen encounter, and redirecting that decision toward apoptosis and downstream regulatory signaling at the moment of transplantation is sufficient to initiate a self-sustaining tolerogenic loop. Sustained FasL expression may be biologically undesirable — FasL has pleiotropic immune regulatory roles systemically, and its expression in vivo is tightly regulated. The clinical product is designed as a transient induction tool, not a chronic immunosuppressant.
🔗 3 TSS Talks That Connect With This One
1. Hirotake Komatsu, MD PhD & Peter Stock, MD PhD — TSS Think Tank, April 30, 2026 📄 Read the paper → American Journal of Physiology — Cell Physiology, 2026 Dr. Komatsu’s pO₂_survival framework — quantifying the oxygen tension at the live-dead boundary within 3D islet spheres — directly addresses the biophysical survival challenge that precedes immune tolerance at extrahepatic sites. SC-islets (pO₂_survival ~0.1–0.4 mmHg) are an order of magnitude more hypoxia-resistant than primary islets (~2–3 mmHg), meaning the cells that survive the acute post-transplant hypoxic window are exactly the cells that Shirwan’s FasL tolerogenic circuit then needs to protect from adaptive immune attack. These two talks address consecutive, complementary barriers: first survive the oxygen crisis, then survive the immune crisis. Understanding both is required to design a complete extrahepatic transplant strategy.
2. Nidheesh Dadheech, PhD — SUNY Upstate Medical University TSS Think Tank, April 2, 2026 ▶️ TSS Substack pregame & resources → Dr. Dadheech’s work on vertical wheel bioreactor manufacturing of SC-islets is the manufacturing counterpart to Shirwan’s transplantation immunology. The Protex FasL-microgel platform requires a defined, consistent SC-islet product to pair with — and the manufacturing consistency Dadheech’s group has established, producing SC-islets in a narrow 100–250 μm size range, is the upstream input that enables meaningful co-transplantation ratios and dose calculations. As the field moves toward first-in-human SC-islet trials that avoid chronic immunosuppression, the immunological protection Shirwan’s platform provides and the scalable, GMP-grade product Dadheech’s bioreactor approach manufactures will need to be co-designed from the start.
3. Fast Tracking Stem Cell-Derived Islets to the Clinic — What Is Needed? State of the Science Panel ▶️ Watch the full panel on YouTube → This panel maps the full regulatory, manufacturing, immunological, and site-of-delivery landscape for SC-islet clinical translation. Shirwan’s FasL-microgel platform is directly relevant to two of the panel’s central challenges: the immunosuppression minimization question (can SC-islet recipients be managed with less chronic immunosuppression, and what strategies enable this?) and the extrahepatic site question (what immunomodulatory approaches are compatible with retrievable intraomental or subcutaneous delivery?). The panel’s identification of localized immune tolerance as a key unmet need in the field maps exactly onto what the Protex platform is designed to provide. This is the essential policy and clinical context for understanding why Shirwan’s biophysical work matters right now.
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