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Engineering AMR-on-a-chip to probe rejection and accommodation pathways

Award Number: R21AI202489
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Engineering AMR-on-a-chip to probe rejection and accommodation pathways - TITLE: Engineering AMR-on-a-chip to probe rejection and accommodation pathways Abstract Kidney transplantation is the preferred treatment for patients with end-stage renal disease (ESRD), offering improved quality of life, reduced long-term mortality and morbidity, and lower healthcare costs compared to dialysis. However, antibody-mediated rejection (AMR) remains a major obstacle to achieve long-term graft survival. Despite its clinical significance, investigating the pathogenesis of AMR remains challenging due to the immunological and physiological complexities of the disease in vivo, and the lack of in vitro models that faithfully replicate its pathological features. To address this unmet need, we aim to develop and validate an AMR-on-a- chip platform to recapitulate key features of AMR in vitro (Aim 1). We have developed a glomerulus-on-a-chip model using human induced pluripotent stem cell (iPSC)-derived renal endothelial cells (ECs) and podocytes. This model successfully mimics the structure and function of the glomerular filtration barrier. To induce AMR, we will incorporate immune components required to its pathogenesis, including pathological antibodies (single anti- HLA Ab, patient derived serum DSA anti-ABO Ab, and autoimmune Ab targeting podocytes), complement, and innate immune cells. Our preliminary data also demonstrate that targeting complement pathways can provide transient protection against AMR in the presence of high levels of donor-specific antibodies (DSAs), suggesting the possibility of inducing a state of accommodation. In addition, we have developed novel endopeptidases capable of selectively cleaving IgM alone or both IgG and IgM. In Aim 2, we will evaluate therapeutic strategies targeting complement and immunoglobulins using our AMR-on-a-chip platform reconstructed with the full spectrum of immune components. Specifically, we will test the efficacy of complement inhibitors (anti-C3 and anti-C5) and novel endopeptidases (IdeS, IceM and IceMG) in mitigating AMR and promoting durable protection of renal endothelial cells and podocytes upon re-exposure to pathological antibodies, a process referred to as accommodation. We hypothesize that downstream signaling triggered by HLA, ABO, or autoimmune antigens, in the absence of complement-mediated injury, may upregulate protective genes in target cells, rendering them resistant to subsequent immune challenges. This study will clarify the roles of pathological antibodies, complement, and innate immune cells in AMR; explore the possibility of antibody-independent mechanisms; and assess the local efficacy of therapeutic agents in preventing AMR in the transplant setting.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $162,792 )
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	1	8/20/2026	NEW	$162,792
														Subtotal = $162,792

Grand Total All Awards = $162,792

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Engineering AMR-on-a-chip to probe rejection and accommodation pathways

Award Number: R21AI202489

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/20/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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