Mouse Models for Studying Human Islet Transplantation

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Mouse Models for Studying Human Islet Transplantation Ronald G. Gill, Joshua Beilke,, Nathan Kuhl,, Michelle Kerklo, and Mark M. Nicolls Barbara Davis Center for Childhood Diabetes University of Colorado Health Science Center

Can a mouse model form an in vivo potency assay?

Mouse Models for Assessing Human Islet Function Immune-suppressed wild-type mice (e.g. anti-cd4) T cell-deficient nude (nu/nu( nu/nu) ) mice Severe-combined immune-deficient (SCID( SCID) Recombinase activating gene 1,2-deficient (Rag( -/- )

Insulin akita Mutation Missense mutation (Cys96Tyr) in Insulin 2 (Ins 2) gene Prevents appropriate folding of pro-insulin Autosomal-dominant (chromosome 7) Functions as a dominant-negative Durable and irreversible hyperglycemia (>450-500mg/dl) 500mg/dl) Males more severe than females

Rag1 -/- akita Blood Glucose AK-1 AK-2 35 30 25 AK-3 AK-4 AK-5 20 15 10 1 2 3 4 5 SZ Blood Glucose Rag1 -/- akita Weight Change ) AK-1 AK-2 AK-3 26 AK-4 AK-5 24 22 20 18 1 5 SZ Streptozotocin Weight 5 Day Weight Change Variability 35 30 25 20 SZ-1 SZ-2 SZ-3 SZ-4 SZ-5 26 24 22 SZ-1 SZ-2 SZ-3 SZ-4 SZ-5 15 10 1 2 3 4 5 20 18 1 5 Day SZ-3 SZ-2 SZ-1 SZ-4 SZ-5 Animal

Utility of akita mice as islet transplant recipients Mathews, CE et al. Transplantation. 73:1333, 2002

Islet Function in C57Bl/6 akita Mice Donor n Graft Function (Days) ISOGRAFTS (C57Bl/6) 8 > 100 (x8) ALLOGRATS (BALB/c) (BALB/c) 3 9, 9, 12

Islet Transplantation in B6 Rag1 -/-akita Mice Donor Islets Transplant 2000 IEQ under the kidney capsule of B6 Rag1 -/-akita Monitor blood glucose Nephrectomy immunohistochemistry

Correlation between in vitro assays and in vivo function in Rag1 -/-akita mice Purity Viability S.I. In vivo function (>30 days) 60 60 1.6 Yes 90 80 3.0 Yes 80 75 5.2 Yes 85 72 2.4 Yes 90 70 2.4 Yes 40 60 0.8 No 60 77 0.2 No 60 60 0.6 No 60 60 2.1 No 75 75 4.0 No 50 60 1.1 Yes

Immune Injury Non-Immune Injury Islets

Isolated Islets Highly Express Proteins Associated with ER-Distress Nicolls, MR et al. J. Proteome. Res. 2:199, 2003

Function of Islet Grafts in Rag1-/- Recipients Donor n Graft Function (days) Mouse 8 >100 (x 8) Rat (WF) 9 >100 (x 9) Porcine Human 12 17 >100 (x 12) 47,65,74,91,94 >100 (x12)

Spontaneous Failure of Human Islets Rag1 -/-akita Mice Blood Glucose (mm) 30 20 10 0 0 50 100 Human Islet Tp#1 Human Islet Tp#2 Normoglycemia Day Post Transplantation

Pathology of Failed Human Islets (day 70) Fibrosis (Tri-Chrome) Amyloid (Thyoflavin S)

Failure of hiapp Transgenic Mouse Islets Plasma Glucose (mg/dl) 600 500 400 300 200 100-10 STZ 0 Tx 10 20 Day 100 tg+ 100 tg- 30 40 50

α α δ α Donor Islet (pre-transp lant) δ α Islet C ell A ttrition in T ransplantatio n 1. M e c ha n ic a l stre s s fro m is le t iso la tio n, infusion and im plantation in ectopic site. 2. Non-im m une response (Specific Aim 1) 3. Inna te im m une re spo nse (S pec ific A im 2) 4. Adaptive im m une response a. Autoim m une response b. A llo im m une re sp o n se 5. Is le t-to x ic im m uno s up p re s s io n 6. Failure of islet revascularization α α δ α Donor Islet (post-transp lant) Figure 1. Factors influencing loss of islet cells following transplantation.

Summary / Conclusions Spontaneously diabetic akita mice demonstrate a stable and irreversible model of hyperglycemia Diabetic akita mice can be readily maintained for 2-33 months prior to transplantation Human islets can reverse diabetes in immune- deficient akita mice (Rag1( -/-akita ) Human islets can spontaneously fail over time from non-immune factors (metabolic distress?)

Collaborators Mark Nicolls Michelle Kerklo Gina Rayat Josh Beilke Nathan Kuhl

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