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Standardization of Islet Isolation and Transplantation Variables to Better Optimize Relevant Proto- Cols and Improve Standardization

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Standardization of Islet Isolation and Transplantation Variables to Better Optimize Relevant Proto- Cols and Improve Standardization “What we think, or what we know, or what we believe is, in the end, of little consequence. The only consequence is what we do.” John Ruskin (1819 - 1900) For my family Till min familj Für meine Familie A családomnak List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Brandhorst, H., Friberg, A., Andersson, H.H., Felldin, M., Foss, A., Salmela, K., Lundgren, T., Tibell, A., Tufveson, G., Korsgren, O., Brandhorst, D. (2009) The importance of tryptic- like activity in purified enzyme blends for efficient islet isola- tion. Transplantation, 87:370-375 II Friberg, A.S., Ståhle, M., Brandhorst, H., Korsgren, O., Brand- horst, D. (2008) Human islet separation utilizing a closed auto- mated purification system. Cell Transplantation, 17:1305-1313 III Friberg, A.S., Brandhorst, H., Buchwald, P., Goto, M., Ricordi, C., Brandhorst, D., Korsgren, O. (2011) Quantification of the islet product: presentation of a standardized current good manu- facturing practices compliant system with minimal variability. Transplantation, 91(6):677-683 IV Friberg, A.S., Lundgren, T., Malm, H., Nilsson, B., Felldin, M., Jenssen, T., Kyllönen, L., Tufveson, G., Tibell, A., Kor- sgren, O. Transplantable functional islet mass – predictive bio- markers of graft function in islet after kidney transplanted pa- tients. Manuscript Reprints were made with permission from the respective publishers. Contents Introduction ........................................................................................... 11 Aims ....................................................................................................... 12 General aims ............................................................................................. 12 Specific aims ............................................................................................. 12 Background ............................................................................................ 13 History of diabetes mellitus ...................................................................... 13 From antiquity to insulin ...................................................................... 13 The big discovery! ................................................................................ 14 Forms of diabetes and epidemiology ........................................................ 15 Transplantation as therapy for diabetes .............................................. 16 Islet transplantation ................................................................................. 18 Short history of clinical islet transplantation ....................................... 18 Islet isolation procedure ........................................................................... 19 Regulatory considerations.................................................................... 19 Islet donors and organ transport ......................................................... 21 Enzymes for islet isolation .................................................................... 21 Islet purification ................................................................................... 23 Islet culture........................................................................................... 24 Islet isolation quality control ................................................................ 26 Measuring clinical success .................................................................... 28 Materials and methods ........................................................................... 31 Results and discussion ............................................................................ 34 Identification of a previously unrecognized enzyme activity (Paper I) ..... 34 Evaluation of enzymatic digestion of rat pancreas .............................. 34 Evaluation of enzymatic digestion of human pancreas ....................... 35 Progress in the field since Paper I was published ................................ 36 Automated gradient making system (Paper II) ........................................ 36 Functionality of pump-made gradients ................................................ 37 Islet separation with pump-made gradients ........................................ 37 Progress in the field since Paper II was published (2008) .................... 38 Digital imaging analysis (DIA) and presentation of a GMP-friendly islet quantification technique (Paper III) .......................................................... 38 DIA validation ....................................................................................... 39 Computer-assisted DIA versus manual methods ................................. 39 Evaluator versus sample variation ....................................................... 39 Closed system islet evaluation ............................................................. 40 Progress in the field since Paper III was published (2011) ................... 40 Prediction of islet graft potency (Paper IV) ............................................... 41 Correlations to short term outcome .................................................... 42 Transplanted functional islet mass (TFIM) model ................................ 43 Conclusions ............................................................................................ 45 Specific conclusions ................................................................................... 45 General conclusion.................................................................................... 45 Critical considerations regarding research design and methods .............. 46 Paper I .................................................................................................. 46 Paper II ................................................................................................. 46 Paper III ................................................................................................ 46 Paper IV ................................................................................................ 47 Future perspectives ................................................................................ 48 Popular science summary ....................................................................... 51 Svensksammanfattning .......................................................................... 53 Acknowledgments .................................................................................. 55 References .............................................................................................. 61 Abbreviations AIRarg Acute insulin response to argentine APS Automated purification system BAEE N-benzoyl-L-arginine-ethyl ester BD Brain death BMI Body mass index C-peptide Connecting-peptide CI Collagenase class I CII Collagenase class II CIT Cold ischemia time CV% Coefficient of variation × 100% CP/GCr Change in C-peptide × glucose-1 × creatinine-1 ratio DM Diabetes mellitus DMC Dimethylcasein DIA Digital imaging analysis DTZ Dithiocarbazone, dithizone ELISA Enzyme-linked immunosorbent assay EP European parliament GMP Good manufacturing practices HbA1c Hemoglobin A1c HTK Histidine-tryptophan-ketogluterate IAK Islet after kidney IE Islet equivalent IL Interleukin IVGTT Intravenous glucose tolerance test MCP-1 Macrophage chemotractant protein-1 MMTT Mixed meal tolerance test NP Neutral protease PP-cells Pancreatic polypeptide cells PZ 4-phenylazobenzyloxycarbonyl-L-prolyl-L- leucylglycyl-L-prolyl-D-arginine SEM Standard error of the mean SGM Standard gradient maker SUIT Secretory units of islet in transplantation T1DM Type 1 diabetes mellitus T2DM Type 2 diabetes mellitus TF Tissue factor TLM Two-layer method UW University of Wisconsin solution Introduction Diabetes is a widespread and increasingly prevalent disease. Currently, - cell replacement therapy via transplantation of islets of Langerhans is a via- ble means to maintain control of blood sugar levels and reduce the risk of hypoglycemia in defined populations of patients with brittle type I diabetes mellitus or those requiring partial or whole pancreatectomy. The process of islet isolation across centers suffers from variability and, despite important advances, remains to be standardized. Standardization of the isolation process, quality control parameters, quantification before transplant, and even variables associated with transplant outcome are needed for meaningful comparisons between labs. In this thesis some variables affecting islet isolation success, evaluation of end product, and short-term islet engraftment are uncovered, addressed and evaluated. A previously disregarded enzyme activity, tryptic-like activity, has been identified to influence pancreas digestion efficiency and islet isola- tion success in both the preclinical and clinical situations. An effectively closed, automated pump system for the consistent and flexible creation of density gradients for separation of islet from non-islet tissue was developed. Islet quantification as evaluated with computer-assisted digital imaging analysis and introduction of a closed system that allows for the evaluation of the entire preparation at once is presented. Establishment of a hereto rela- tively unused transplant evaluation parameter, CP/GCr, was used to identi- fy donor, islet isolation, and quality control variables associated with early graft function in an islet after kidney patient population. Through standardization, isletologists will be better equipped to advance the field more cheaply
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