Review of experimental attempts of islet allotransplantation in rodents: Parameters involved and viability of the procedure

Table 1 Description of the experimental studies on allografts in rodents

Ref.	Donor/recipient	Immunosuppression	Allotransplantation site	Graft survival time
Fotiadis et al[9]	Lewis→ Wistar	Mycophenolate mofetil (MMF) and Cyclosporine A (CsA)	Spleen	N/A
Merani et al[10]	Lewis →Wistar	AEB-071 (Protein kinase C inhibitor) + CsA, CTLA4-Ig, MMF	Kidney capsule	100 d
Nishimura et al[11]	C57BL/6 → Balb/c	Tacrolimus	Nonmetallic dorsal skinfold chamber	N/A
Makhlouf et al[12]	C57BL/6/Balb/c	Blockade of CD28:B7 and anti-CD40L; CTLA-4	Kidney capsule	1 wk
Salazar-Bañuelos et al[13]	Wistar →Sprague Dawley	No immunosuppression	Medullary channel	21 d
Wee et al[14]	Lewis → Fisher	CsA + Tautomycetin (synergist)	Liver (portal vein)	Control group - 5.2 ± 0.5 d TMC - 5.1 ± 0.9 d TMC (0.03 mg/kg) + CsA (5 mg/kg) - > 41 d TMC (0.1 mg/kg) + CsA (5 mg/kg) - 103.8 ± 56.8 d
Plesner et al[15]	Balb/c →EBA	No immunosuppression	Kidney capsule	60 d
Watanabe et al[16]	Balb/c → C57BL/6	Tacrolimus and DHMEQ (NF-κB inhibitor)	Kidney capsule	100 d
Gysemans et al[17]	Balb/c→ C57BL/6	No immunosuppression	Kidney capsule	9.2 ± 4.9 d (Autoimmune diabetes) 15 ± 3 d (Not chemically diabetic autoimmune)
Xekouki et al[18]	Wistar→Lewis	CsA and MMF	Spleen (parenchyma)	8 d (CsA) 10.92 d (MMF 1) 11 d (MMF 2)
Baker et al[19]	A/J→ C57Bl/6J	Monoclonal antibody antiBIP-10	Kidney capsule	19.7 ± 2.3 d (C57Bl/6J) 20.2 ± 2.7 d (CXCR3-/-C57Bl/6J
Li et al[20]	FVB→ Balb/c	No immunosuppression	Kidney capsule	N/A
Vieiro et al[21]	C57Bl/6→ C3H	Tritiated thymidine (preoperative) and CsA	Subcutaneous	N/A
Neuzillet et al[22]	C3H → Balb/c	No immunosuppression	Kidney capsule	13.8-27.5 d
Melzi et al[23]	C57Bl/6 → Balb/c	Rapamycin+ FK506+ anti-IL- 2Ra chain mAbs and rapamycin+IL-10	Kidney capsule	> 100 d
Fiorina et al[24]	Balb/c→ C57Bl/6	No immunosuppression	Kidney capsule	14 d
Fan et al[25]	C57Bl/6 → Balb/c	LTß R-Ig, CTLA4-Ig or LTR mAb anti mouse		LTβ R-Ig- 27 d CTLA4-Ig- 55 d LTβ R-Ig+CTLA4-Ig - > 100 d LTR mAb anti mouse - 11 d
Jung et al[26]	Balb/c → C57Bl/6	CD154 mAb (MR1) anti mouse and ROS-A (Reactive Oxygen Specie - A)	Kidney capsule	ROS-A - 53 d MR1 - 82 d ROS-A+MR1 - > 160 d
Påhlman et al[27]	Balb/c → C57Bl/6J	AR-C117977 (10 or 30 mg/kg) or CsA 20 mg/kg	Kidney capsule	CsA - 16 d AR-C117977, 10 mg/kg - >100 d AR-C117977, 30 mg/kg -29,33 d
Wang et al[28]	Balb/c → C57Bl/6	B7-H4 and Ad-LacZ	Kidney capsule	B7-H4 - approximately 60 d Ad-LacZ - approximately > 20 d
Chen et al[29]	Sprague Dawley → Lewis	No immunosuppression	Intra-abdominal	8 wk
Giraud et al[30]	C3H → Balb/c	No immunosuppression	Kidney capsule	SCOT + PEG 20 kDa ³10 g/L - 20 d, CMRL-1066 + 1% BSA - 17.5 ± 1 d, Solution UW - 17.2 ± 0.4 d, SCOT without PEG - 14 ± 0.9 d Solution HBSS + 0.5% BSA - 14 ± 0.7 d
Qi et al[31]	Wistar/Lewis → Lewis	No immunosuppression	Intraperitoneal (Macroencapsulated) Kidney capsule (not macroencapsulated)	24 wk (Macroencapsulated) 48 h (not macroencapsulated)
Potiron et al[32]	Wistar → C57Bl/6	CTLA4 Ig or CD40 Ig	Kidney capsule	24.3 ± 9.7 d
Jahr et al[33]	Lewis → Wistar	Anti-rat antilymphocyte serum	Liver (portal vein)

N/A: Not available.

Table 2 Sites of islet infusion based on the literature from the PubMed database

Sites of islet infusion	Literature from the PubMed database
Kidney capsule	70%
Liver	23%
Other sites1	7%

¹Subcutaneous, bone marrow, sub-retinal space, sub-conjunctival space, spleen, intraperitoneal cavity and sub-mucosal space of the duodenum.

Table 3 Comparative analysis of the different types of rodents used and their basic characteristics-Age and Weight

Ref.	Donor/recipient	Age	Weight
Fotiadis et al[9]	Lewis→ Wistar	N/A	220 g-300 g
Merani et al[10]	Lewis→ Wistar	N/A	200 g (male)/150 g (female)
Nishimura et al[11]	C57BL/6 → Balb/c	9-12 wk /8-12 wk	N/A
Makhlouf et al[12]	C57BL/6→ Balb/c	6-8 wk (male)/ N/A	N/A
Salazar-Bañuelos et al[13]	Wistar→ Sprague Dawley	N/A	260-326 g
Wee et al[14]	Lewis→ Fisher	10-12 wk	N/A
Plesner et al[15]	Balb/c→ EBA	8-10 wk /N/A	N/A
Watanabe et al[16]	Balb/c→ C57BL/6	10-14 wk /male	N/A
Gysemans et al[17]	Balb/c→ C57BL/6	(8-21 d) → (> 180 d)	N/A
Xekouki et al[18]	Wistar→Lewis	N/A/male	220-300 g
Baker et al[19]	A/J→ C57Bl/6J	8-12 d/male	N/A
Li et al[20]	FVB→ Balb/c	8-12 wk	N/A
Vieiro et al[21]	C57Bl/6→ C3H	N/A	N/A
Neuzillet et al[22]	C3H → Balb/c	N/A	N/A
Melzi et al[23]	C57Bl/6 → Balb/c	9 wk (female) → 9 wk (female)	20-22 g
Fiorina et al[24]	Balb/c→ C57Bl/6	N/A	N/A
Fan et al[25]	C57Bl/6 → Balb/c	N/A - adults (female)	N/A
Jung et al[26]	Balb/c → C57Bl/6	12 wk (male) → 12 wk (male)	25-30 g
Påhlman et al[27]	Balb/c → C57Bl/6J	N/A - (female)	N/A
Wang et al[28]	Balb/c → C57Bl/6	8-10 wk (female) → 8-10 wk	N/A
Chen et al[29]	Sprague Dawley → Lewis	N/A (male)	250-350 g → 196 ± 15 g
Giraud et al[30]	C3H → Balb/c	6 wk	N/A
Qi et al[31]	Wistar/Lewis → Lewis	9-10 wk (male)	250-300 g
Potiron et al[32]	Wistar → C57Bl/6	N/A (male)	200-300 g
Jahr et al[33]	Lewis → Wistar	N/A (male) → N/A (male)	310-330 g→ 215-245 g

N/A: Not available.

Table 4 Analysis of the immunosuppressant drugs used at international islet transplantation research centers

Immunosuppressant	Number of centers using theimmunosuppressant(based on data from the literature)
CsA	6
MMF	3
CTLA4 Ig	4
CD40 Ig	2
NF-kB Inhibitor (DHMEQ)	1
Anti-CD154 mAb (MR1)	2
Tritiated thymidine	1
Tacrolimus	1
Blockade of CD28:B7	1
Tautomycetin	1
Protein Kinase C Inhibitor (AEB-071)	1
Monoclonal antibody anti-BIP-10	1
Rapamycin+FK506+anti–IL-
2Ra chain mAbs, n31 and rapamycin+IL-10; n29	1
LTβ R-Ig	1
LTR mAb	1
ROS-A	1
AR-C117977	1
B7-H4 and Ad-LacZ	1
Anti-rat antilymphocyte serum	1
No immunosuppression	9

Table 5 Quantitative analysis of immunosuppressant drugs use

Ref.	Immunosuppression	Dose	Administration frequency
Fotiadis et al[9]	MMF and CsA	12 mg/kg and 23 mg/kg (MMF) 5 mg/kg (CsA)	-
Merani et al[10]	AEB-071 (Protein Kinase C Inhibitory) + CsA, CTLA4-Ig, MMF	30 mg/kg (AEB-071) 2.5 mg/kg and 5 mg/kg (CsA) 0.25 mg (CTLA4-Ig Intraperitoneal) 10 mg/kg (MMF)	2 times a day, oral (AEB-071) 2 times a day, oral (CsA) 0, 2, 4 and 6 PO, Intraperitoneal (CTLA4-Ig) Once a day, oral (MMF)
Nishimura et al[11]	Tacrolimus	0.5 mg/kg	Infused subcutaneously - Daily - for 14 d
Makhlouf et al[12]	Blockade of CD28:B7 and anti-CD40 L; CTLA-4	250μg	Intraperitoneal - 0, 2, 4 and 6 PO
Wee et al[14]	CsA+Tautomycetin (Synergist)	5 mg/g and 15 mg/kg (CsA)	Once a day for 7 d
Watanabe et al[16]	Tacrolimus and DHMEQ	1.5 mg/kg (Tacrolimus) 20 mg/kg (DHMEQ)	Once a day 0 to 3 PO and 2 times a day 0 to 14 PO (DHMEQ); 0 to 14 PO (Tacrolimus); Once a day 0 to 3 PO (DHMEQ)+0 to 14 PO (Tacrolimus)
Xekouki et al[18]	CsA and MMF1	5 mg/kg (CsA) 12 mg/kg (MMF) 23 mg/kg (MMF)	Oral - Daily - 12 consecutive days
Baker et al[19]	Monoclonal antibody antiBIP-10	300 μg intraperitoneal	Daily - 14 d1
Vieiro et al[21]	Tritiated thymidine (preoperative) and CsA	20 mg/kg (CsA)	N/A
Melzi et al[23]	Rapamycin + FK506 + anti–IL-2Ra chain mAbs and rapamycin+IL-10	1 mg/kg (Rapamycin) 0.05 μg/kg (IL-10) 0.3 mg/kg (FK506) 1 mg/kg (mAbs)	Intraperitoneal: Once a day - 30 PO (Rapamycin) 2 times a day - 30 d (IL-10) Once a day - 30 d (FK506) 0.4 PO (mAbs)
Fan et al[25]	LTβ R-Ig, CTLA4-Ig or LTR mAb anti mouse	200 μg	Intraperitoneal- days -1, 1, 3, 5, 7 and 9
Jung et al[26]	CD154 mAb (MR1) anti mouse + ROS-A	250 μg (CD154 mAb (MR1) anti mouse) 200 mg/kg of Ros A	Intraperitoneal injection 0, 2, 4, 6 and 8 PO (CD154 mAb (MR1) anti mouse) 8 consecutive days (ROS-A)
Påhlman et al[27]	AR-C117977 or CsA	0.2 mL - 3, 10, 30, or 100 mg/kg (AR-C117977) 0.5 mL - 20 mg/kg (CsA)	Subcutaneous - once a day 0 to 9 PO (AR-C117977) Once a day 0-9 PO or 0-39 PO (CsA)
Wang et al[28]	B7-H4	5 plaque-forming units (pfu) of Ad-B7-H4 or Ad-LacZ	N/A
Potiron et al[32]	CTLA4 Ig or CD40 Ig	5 109 IP of AdCTLA4 IM and/or 5 109 IM or 2 109 IV of AdCD40Ig; IM administration: 10 μL per point (3 points) IV administration: 150 μL with 0.9% sodium chloride	IM administration - anterior tibialis muscle; IV administration - venile vein
Jahr et al[33]	Anti-rat antilymphocyte serum	Intraperitoneal administration 0.5 mL	1 d after islet transplantation

¹First dose administered 4 h preoperatively. N/A: Not available; MMF: Mycophenolate mofetil; CsA: Cyclosporine A.

Table 6 Analysis of induction and treatment of diabetic process with islet transplantation

Ref.	Number oftransplanted islets	Diabetes induction method	Hyperglycemia induction (preoperative)	Normalization of hyperglycemia (postoperative)	Graft rejection	Criteria for primary graft dysfunction (PGD)
Fotiadis et al[9]	1812 ± 145	Streptozotocin (60 mg/kg) + PBS-Solution (Phosphate Buffer Solution) - 10 mg/mL (pH 4,5);	7 d	3 d	12 d (MMF) 10 d (CsA)	Glucose above 200 mg/dL; after 2nd PO 2 consecutive times
Merani et al[10]	1500	Streptozotocin (75 mg/kg) intraperitoneal	5 d	3 d	22 d	Glucose above 324 mg/dL after 2 consecutive days
Nishimura et al[11]	2-10/dorsal skinfold chamber	-	-	-	N/A	-
Makhlouf et al[12]	350 (Balb/c) 700 (NOD)	Streptozotocin and spontaneously (225 mg/kg in peritoneal cavity)	2 wk	3 d	10 d (Balb/c)	200 mg/dL - 2 to 3 consecutive days
					5 d (NOD) and 7 d complete rejection (NOD)
Salazar-Bañuelos et al[13]	840 (of Wistar)	-	-	-	N/A1	N/A
Wee et al[14]	4000	Streptozotocin (35 mg/kg)	N/A	N/A	Untreated - 5.2 d (± 0.5)	200 mg/dL after 2 consecutive days
					TMC - 5, 1 d (± 0, 9)
					TMC (0.03 mg/kg) + CsA (5 mg/kg) - > 41 d
					TMC (0.1 mg/kg) + CsA (5 mg/kg) - 103.8 ± 56.8 d
Plesner et al[15]	550	Streptozotocin (375 mg/dL) intraperitoneal	3-5 d	5 d1	60 d	≥ 198 mg/dL after 2 consecutive days
Watanabe et al[16]	600 or 300	Streptozotocin (180 mg/kg) intraperitoneal	5-7 d	N/A	69 d (Tacrolimus)	> 350 mg/dL for 2 consecutive days
					100 d (DHMEQ 3 d and Tacrolimus 14 d)
Gysemans et al[17]	300	Alloxan (90 mg/kg)	24 h	N/A	N/A - 23%	Glucose level > 200 mg/dL more than 3 consecutive days
Xekouki et al[18]	2000	Streptozotocin (60 mg/kg) diluted in phosphated solution 10 mg/mL	1 wk	N/A	7 d (MMF ´1)	-
Baker et al[19]	300	Streptozotocin (220 mg/kg)	N/A	N/A	7 d	-
Li et al[20]	400 (200/Kidney capsule)	Streptozotocin (220 mg/kg)	N/A	N/A	8.36 ± 1.67 (islets of FVB)	Glucose levels > 250 mg/dL - 2 consecutive measurements
					16.2 ± 2.52 (islets of MT)
Vieiro et al[21]	200	Streptozotocin (270 mg/kg) intraperitoneal	N/A	N/A	3-7 d	≥ 250 mg/dL - 3 consecutive measurements
Neuzillet et al[22]	550	N/A	N/A	4 h	PEG-Solution 8 kDa 27.50 ± 3.70 d; PEG PEG-Solution 20 kDa 23.13 ± 4.39 d; PEG-Solution 35 kDa 13.80 ± 3.49 d	> 199.8 mmol/L - 2 consecutive measurements
Melzi et al[23]	400	175 a 200 mg/kg intravenous	1-2 wk	5 d	29 d (mouse with Glucose levels < 450 mg/dL) and 16 d (mouse with Glucose levels > 450 mg/dL)	> 250 mg/dL - 2 consecutive measurements on postoperative
Fiorina et al[24] Fan et al[25]	NA 500	Streptozotocin	N/A N/A	N/A N/A	14 d 27 d (LT[α]R-Ig) 55 d (CTLA4-Ig) After 100 d or more (LT[β]R-Ig and CTLA4-Ig)	N/A > 300 mg/dL- after 2 consecutive days
		Streptozotocin
		(200 mg/kg)
Jung et al[26]	300 IEQ	Streptozotocin (180 mg/kg)	N/A	1 d	ROS-A - 53 d MR1 - 82 d ROS-A+MR1 - > 160 d	> 200 mg/dL - 2 consecutive measurements on the same week
Påhlman et al[27]	500-600	Alloxan	N/A	N/A	CsA - 16 d	N/A
		Intravenous			AR-C117977, 10 mg/kg - > 100 d AR-C117977, 30 mg/kg - 29, 33 d
Wang et al[28]	400	Streptozotocin (200 mg/kg)	3-4 d	3 d	B7-H4 - approximately 60 d	> 250 mg/dL after primary graft success
					Ad-LacZ - approximately > 20 d
Chen et al[29]	3000 IEQ	Streptozotocin dissolved in saline (50 mg/kg)	N/A	1 wk	13 wk (SGA - microencapsulated) 7 wk (ABa- microencapsulated) 5 wk (APA- microencapsulated)	N/A
Giraud et al[30]	1400 IEQ	Streptozotocin (250 mg/kg), intraperitoneal	N/A	N/A	SCOT + PEG - Solution 20 kDa ³10 g/L - 20 d, CMRL-1066 + 1% BSA - Solution 17.5 ± 1 d, UW-Solution - 17.2 ± 0.4 d, SCOT without PEG -14 ± 0.9 d HBSS + 0.5% BSA - Solution - 14 ± 0.7 d	> 200 mg/dL - 2 consecutive measurements
Qi et al[31]	1940 (± 39)	Streptozotocin (55 mg/kg)	7 d	N/A	N/A	N/A
Potiron et al[32]	800-1000	Streptozotocin (180 mg/kg)	1 wk	4 d	24.3 ± 9.7 d	250 mg/dL on 2 successive measurements
Jahr et al[33]	700-900	Streptozotocin (55 mg/kg)	7-10 d	Right after transplantation	1 wk	> 300 mg/dL after 8.9 ± 0.7 d

¹Rodents that had normalized blood glucose in 5 d were included in the study. N/A: Not available; IEQ: Islet equivalents.

Table 7 Analysis of the parameters of hyperglycemia

Ref.	Blood Glucose Levels: hyperglycemia (mg/dL)
Fotiadis et al[9]	180 on 2 consecutive measurements
Merani et al[10]	180 on 3 consecutive days
Makhlouf et al[12]	Moderate diabetes: between 240 and 350
	Severe diabetes: between 351 and 550
	Very severe diabetes: more than 550
Wee et al[14]	200
Plesner et al[15]	≥ 360
Watanabe et al[16]	200 on 2 consecutive days
Gysemans et al[17]	200 on 2 consecutive days
Xekouki et al[18]	300
Baker et al[19]	300 on 3 consecutive days
Li et al[20]	350 to 500 after 2 consecutive measurements
Melzi et al[23]	250 on 2 consecutive measurements
Fan et al[25]	300 on 2 consecutive measurements
Jung et al[26]	300 on 2 consecutive days
Påhlman et al[27]	288 on 2 consecutive measurements
Wang et al[28]	300 after 2 consecutive days
Chen et al[29]	302.4 on more than 3 consecutive days
Giraud et al[30]	350 after 2 consecutive days
Qi et al[31]	450
Potiron et al[32]	> 200