# Anti-inflammatory therapy to improve outcomes in patients with chronic pancreatitis undergoing total pancreatectomy with islet autotransplant (TPIAT)

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $390,847

## Abstract

Abstract
For patients with severe pancreatitis refractory to medical and endoscopic therapy, total pancreatectomy (TP)
with islet autotransplantation (IAT) may be considered. While 90% of TPIAT recipients have some function of
the transplanted islet graft, only about 1/3rd come completely off insulin. The long-term goal of the proposed
research is to develop new therapies that will increase the number of patients who are non-diabetic following
islet autotransplant. Such therapies may also benefit recipients of islet allotransplant for type 1 diabetes.
Following islet transplantation, the islets must acutely survive the stress of the procedure, and then they must
engraft in the liver and establish a vascular supply. The greater the functional islet mass engrafted, the lower
the risk of post-operative diabetes. It has been estimated that more than half of the islet mass may be lost in
the early post-transplant period in islet transplant recipients. Beta cell apoptosis is common during the first
month post-transplant and is upregulated in the presence of inflammatory cytokines such as TNFα. Thus, a
major contributor to islet loss is the inflammatory damage sustained by the transplanted islets in the early
post-transplant period; we propose to directly target this destructive process.
Two promising anti-inflammatory therapies are available to address this problem: (1) the TNFα inhibitor
etanercept and (2) the serine protease inhibitor alpha-1 antitrypsin. Both agents are commercially available for
clinical trials. Proof-of-principle for etanercept has been demonstrated in type 1 diabetic allotransplant
recipients, in whom a 10 day course of etanercept early post-transplant significantly improved long-term insulin
independence, due to better survival of the transplanted beta cell mass in the engraftment period. Alpha-1
antitrypsin (A1AT) reduces inflammatory cytokines, protects against cytokine-induced beta cell apoptosis,
and prolongs islet graft survival in mice and intraportal IAT non-human primates.
This initial 3-arm drug-treatment clinical trial will investigate the use of Etanercept and A1AT to improve IAT
function at 90 days and 1 and 2 years post-TPIAT compared to standard care. Forty-five patients undergoing
TPIAT will be randomized 1:1:1 to receive either: 1) etanercept (50 mg on day 0; 25 mg on days 3, 7, 10, 14,
and 21), 2) alpha-1 antitrypsin (90 mg/kg IV days -1, +3, 7, 14, 21, 28) or 3) standard care. Patients will have
mechanistic assessments drawn in the early post-operative period including inflammatory cytokines and
chemokines and measures of beta cell loss. Metabolic testing will occur at 90, 365, and 730 days post-TPIAT,
including mixed meal tolerance testing, IV glucose tolerance testing, and glucose-potentiated arginine-induced
insulin secretion (GPAIS). The latter measures the maximally stimulated acute insulin response (AIRmax) as
the best estimate of islet mass and the primary endpoint (at day 90) for this study. Results wil...

## Key facts

- **NIH application ID:** 9970280
- **Project number:** 5R01DK109914-05
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Melena D. Bellin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,847
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970280

## Citation

> US National Institutes of Health, RePORTER application 9970280, Anti-inflammatory therapy to improve outcomes in patients with chronic pancreatitis undergoing total pancreatectomy with islet autotransplant (TPIAT) (5R01DK109914-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970280. Licensed CC0.

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