Abstract

This application will address two major issues limiting the effective application of human islet allo-transplantation: 1) decreased islet mass from procurement and implantation induced damage, and 2) allo- and tissue-specific immune destruction of transplanted islets. The investigators hypothesize that optimal recovery techniques combined with novel in vitro manipulations will produce superior islets for transplantation that will be resistant to destruction during the procurement and implantation phase of the transplant. They further believe that a short course immune modulation based around a monoclonal antibody specific for CD4 will be superior to long term immuno-suppression in preventing islet rejection. The investigators propose to use established techniques for islet isolation in concert with a novel in vitro islet modification (caspase inhibition) aimed at interrupting the events leading to islet apoptosis. They will implant these islets into patients treated with a non-depleting anti-CD4 monoclonal antibody. Other manipulations including DR haplotype shared transfusion will be used in competing cohorts of patients. Patients will be monitored for their immune responsiveness towards the islet allo-graft, and the islets will be evaluated by biopsy. The function of the islets will be evaluated to determine the success of their interventions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056962-02
Application #
6381703
Study Section
Special Emphasis Panel (ZRG1-IMS (02))
Program Officer
Eggerman, Thomas L
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$598,154
Indirect Cost

  Institution

Name
Justus Liebig University of Giessen
Department
Type
DUNS #
City
Giessen
State
Country
Germany
Zip Code

  Publications

Ang, Meidjie; Meyer, Christian; Brendel, Mathias D et al. (2014) Magnitude and mechanisms of glucose counterregulation following islet transplantation in patients with type 1 diabetes suffering from severe hypoglycaemic episodes. Diabetologia 57:623-32
Drobinskaya, Irina; Linn, Thomas; Saric, Tomo et al. (2008) Scalable selection of hepatocyte- and hepatocyte precursor-like cells from culture of differentiating transgenically modified murine embryonic stem cells. Stem Cells 26:2245-56
Brandhorst, Daniel; Kumarasamy, Vidya; Maatoui, Adel et al. (2006) Porcine islet graft function is affected by pretreatment with a caspase-3 inhibitor. Cell Transplant 15:311-7
Brandhorst, D; Iken, M; Brendel, M D et al. (2005) Long-term preservation of the pig pancreas by a one-layer method for successful islet isolation. Transplant Proc 37:229-30
Brandhorst, D; Iken, M; Brendel, M D et al. (2005) Adaption of neutral protease activity for islet isolation from the long-term two-layer method-stored pig pancreas. Transplant Proc 37:458-9
Staiger, K; Stefan, N; Staiger, H et al. (2005) Adiponectin is functionally active in human islets but does not affect insulin secretory function or beta-cell lipoapoptosis. J Clin Endocrinol Metab 90:6707-13
Meyer, Christian; Saar, Petra; Soydan, Nedim et al. (2005) A potential important role of skeletal muscle in human counterregulation of hypoglycemia. J Clin Endocrinol Metab 90:6244-50
Brandhorst, H; Brendel, M D; Eckhard, M et al. (2005) Influence of neutral protease activity on human islet isolation outcome. Transplant Proc 37:241-2
Brandhorst, H; Alt, A; Huettler, S et al. (2005) The ratio between class II and class I collagenase determines the amount of neutral protease activity required for efficient islet release from the rat pancreas. Transplant Proc 37:215-6
Brandhorst, D; Olbrich, M; Alt, A et al. (2005) Timing of hyperthermic preconditioning affects islet resistance against inflammation. Transplant Proc 37:231-2

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