Parameters involved and viability of immunosuppression on islet allotransplantation procedure in rodents

Iuamoto, Leandro R.; Meyer, Alberto; Chaib, Eleazar; D'Albuquerque, Luiz AC

doi:10.5935/MedicalExpress.2014.04.06

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REVIEW • MedicalExpress (São Paulo, online) 1 (4) • Aug 2014 • https://doi.org/10.5935/MedicalExpress.2014.04.06 copy

Parameters involved and viability of immunosuppression on islet allotransplantation procedure in rodents

Authorship SCIMAGO INSTITUTIONS RANKINGS

INTRODUCTION:

Autoimmunity and rejection after transplantation must still be overcome in the technical development of islet transplantation for the treatment of type 1 diabetes. It is therefore necessary to inhibit rejection of islet grafts while maintaining the graft's ability to secrete insulin. Although the use of immunosuppressants reduces the acute rejection rate in transplant patients, long-term side effects must be prevented.

OBJECTIVES:

The aim of the present study is to organize and analyze the parameters of immunosuppression involved in experimental attempts of allotransplantation in rodents.

METHODOLOGY:

This review was performed using the Pubmed database to search for published articles containing the keywords "rodent islet transplantation". The inclusion criteria involved allotransplantation with rodents' islets and the reference lists of the publications retrieved that were eligible. The exclusion criteria involved isotransplantation, autotransplantation, and xenotransplantation such as transplantation in other species.

RESULTS:

Twenty studies related to allotransplantation were selected for this systematic review based on immunosuppression.

CONCLUSION:

New immunosuppressive drugs increased the survival rates of allotransplantation in rodents by reducing the side effects. The advances in immunosuppression raise the possibility of overcoming autoimmunity and rejection after allotransplantation.

KEYWORDS:
islet transplantation; allograft; immunosuppressive therapy

Immunosuppressant	Number of centers using the immunosuppressant (based on data from the literature)
CsA	6
MMF	3
CTLA4lg	3
CD40lg	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	1
Inhibitory (AEB-071)
Monoclonal antibody antiBIP-10	1
Rapamycin + FK506 +	1
anti-IL-2Ra chain mAbs,
n31 e rapamycin + IL-10; n29
LTβ R-lg	1
LTRmAb	1
ROS-A	1
AR-C117977	1
B7-H4 and Ad-LacZ	1
Anti-rat antilymphocyte serum	1
No immunosuppression	8

Authors	Immunosuppression	Dose	Administration frequency
Fotiadis et al.⁹9 Fotiadis C, Xekouki P, Papalois AE, Antonakis PT, Sfiniadakis I, Flogeras D, et al. Effects of mycophenolate mofetil vs cyclosporine administration on graft survival and function after islet allotransplantation in diabetic rats. World J Gastroenterol. 2005;11(18):2733-8.	MMF and CsA	12 mg/kg and 23 mg/kg (MMF)	-
		5 mg/kg (CsA)
Merani et al. ¹⁰10 Merani S, Pawlick RL, Edgar RL, Toso C, Emamaullee J, Anderson CC, et al. Protein kinase C inhibitor, AEB-071, acts complementarily with cyclosporine to prevent islet rejection in rats. Transplantation. 2009;87(1):59-65.	AEB-071 (Protein Kinase C Inhibitory) + CsA, CTLA4-lg, MMF	30 mg/kg (AEB-071)	2 times a day, oral (AEB-071)
		2.5 mg/kg and 5 mg/kg (CsA)	2 times a day, oral (CsA)
		0.25 mg (CTLA4-lg Intraperitoneal)	0, 2, 4 and 6 PO, Intraperitoneal (CTLA4-lg)
		10 mg/kg (MMF)	Once a day, oral (MMF)
Nishimura et al. ¹¹11 Nishimura R, Nishioka S, Fujisawa I, Shiku H, Shimada M, Sekiguchi S, et al. Tacrolimus inhibits the revascularization of isolated pancreatic islets. PLoS One. 2013;8(4):e56799.	Tacrolimus	0.5 mg/kg	Infused subcutaneously - Daily - for 14 days
Makhlouf et al. ¹²12 Makhlouf L, Duvivier-Kali VF, Bonner-Weir S, Dieperink H, Weir GC, Sayegh MH. Importance of hyperglycemia on the primary function of allogeneic islet transplants.. Transplantation 2003;76(4):657-64.	Blockade of CD28:B7 and anti-CD40 L; CTLA-4	250 µg	Intraperitoneal - 0, 2, 4 and 6 PO
Wee et al. ¹³13 Wee YM, Choi MY, Kang CH, Kim YH, Kim JH, Lee SK, et al. The synergistic effect of Tautomycetin on Cyclosporine A-mediated immunosuppression in a rodent islet allograft model. Mol Med. 2010;16(7-8):298-306.	CsA + Tautomycetin (Synergist)	5 mg/g and 15 mg/kg (CsA)	Once a day for 7 days
Watanabe et al. ¹⁴14 Watanabe M, Yamashita K, Kamachi H, Kuraya D, Koshizuka Y, Shibasaki S, et al. Efficacy of DHMEQ, a NF-kB inhibitor, in islet transplantation: II. Induction DHMEQ treatment ameliorates subsequent alloimmune responses and permits long-term islet allograft acceptance.. Transplantation 2013;96(5):454-62.	Tacrolimus and DHMEQ	1.5 mg/kg (Tacrolimus)	Once a day 0 to 3 PO and
		20 mg/kg (DHMEQ)	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. ¹⁵15 Xekouki P, Papalois A, Fotiadis C, Sfiniadakis J, Karampela E, Papadopoulou A, et al. In vivo test of two low doses of mycophenolate mofetil in an experimental model of islet allotransplantation. Transplant Proc. 2002;34(5):1446-8.	CsA and MMF^* * First dose administered 4 hours preoperatively; N/A = not available.	5 mg/kg (CsA)	Oral - Daily - 12 consecutive days
		12 mg/kg (MMF)
		23 mg/kg (MMF)
Baker et al. ¹⁶16 Baker MS, Chen X, Rotramel AR, Nelson JJ, Lu B, Gerard C, et al. Genetic deletion of chemokine receptor CXCR3 or antibody blockade of its ligand IP-10modulates posttransplantation graft-site lymphocytic infiltrates and prolongs functional graft survival in pancreatic islet allograft recipients. Surgery. 2003;134(2):126-33.	Monoclonal antibody antiBIP-10	300 µg intraperitoneal	Daily - 14 days^* * First dose administered 4 hours preoperatively; N/A = not available.
Vieiro et al. ¹⁷17 Vieiro M, Ceballos C, Barrionuevo P, Hyon SH, Isturiz M, Argibay P. Inhibition of allospecific response in pancreatic islet transplantation: the glycan approach.. Transplant Proc 2005;37(1):242-4.	Tritiated thymidine (preoperative) and CsA	20 mg/kg (CsA)	N/A
Melzi et al. ¹⁸18 Melzi R, Battaglia M, Draghici E, Bonifacio E, Piemonti L. Relevance of hyperglycemia on the timing of functional loss of allogeneic islet transplants: implication for mouse model.. Transplantation 2007;83(2):167-73.	Rapamycin + FK506 + anti-IL-2Ra chain mAbs and rapamycin + IL-10	1 mg/kg (Rapamycin)	Intraperitoneal: Once a day - 30 PO (Rapamycin)
		0.05 µg/kg (IL-10)	2 times a day - 30 days (IL-10)
		0.3 mg/kg (FK506)	Once a day - 30 days (FK506)
		1 mg/kg (mAbs)	0.4 PO (mAbs)
Fan et al. ¹⁹19 Fan K, Wang H, Wei H, Zhou Q, Kou G, Hou S, et al. Blockade of LIGHT/HVEM and B7/CD28 signaling facilitates long-term islet graft survival with development of allospecific tolerance.. Transplantation 2007;84(6):746-54.	LTß R-lg, CTLA4-lg or LTR mAb anti mouse	200 µg	Intraperitoneal - days - 1, 1, 3, 5, 7 and 9
Jung et al. ²⁰20 Jung da Y, Kim EY, Joo SY, Park JB, Moon C, Kim SH, et al. Prolonged survival of islet allografts in mice treated with rosmarinic acid and anti- CD154 antibody. Exp. Mol Med 2008;40(1):1-10.	CD154 mAb (MR1) anti mouse + ROS-A	250 µg (CD154 mAb (MR1) anti mouse)	Intraperitoneal injection 0, 2, 4, 6 and 8 PO
		200 mg/kg of Ros A	(CD154 mAb (MR1) anti mouse)
			8 consecutive days (ROS-A)
Påhlman et al. ²¹21 Påhlman C, Malm H, Qi Z, Veress B, Ferguson D, Bundick R, et al. Operational tolerance in nonvascularized transplant models induced by AR-C117977, a monocarboxylate transporter inhibitor.. Transplantation 2008;86(8):1135-8.	AR-C117977 or CsA	0.2 mL - 3, 10, 30, or 100 mg/kg (AR-C117977)	Subcutaneous - once a day 0 to 9 PO (AR-C117977)
		0.5 ml - 20 mg/kg (CsA)	Once a day 0-9 PO or 0-39 PO (CsA)
Wang et al.²²22 Wang X, Hao J, Metzger DL, Mui A, Ao Z, Verchere CB, et al. Local expression of B7-H4 by recombinant adenovirus transduction in mouse islets prolongs allograft survival.. Transplantation 2009;87(4):482-90.	B7-H4	5 plaque-forming units (pfu) of Ad-B7-H4 or Ad-LacZ	N/A
Potiron et al.²³23 Potiron N, Chagneau C, Boeffard F, Soulillou JP, Anegon I, Le Mauff B. Adenovirus-mediated CTLA4Ig or CD40Ig gene transfer delays pancreatic islet rejection in a rat-to-mouse xenotransplantation model after systemic but not local expression. Cell Transplant. 2005;14(5):263-75.	CTLA4 lg or CD40 lg	5 x 10^9 IP of AdCTLA4 IM and/or 5 x 10^9 IM or 2 x 10^9 IV of AdCD40lg;	IM administration - anterior tibialis muscle; IV administration - venile vein
		M administration: 10 µl per point (3 points)
		IV administration: 150 µl with 0.9% sodium chloride
Jahretal. ²⁴24 Jahr H, Hussmann B, Eckhardt T, Bretzel RG. Successful single donor islet allotransplantation in the streptozotocin diabetes rat model. Cell Transplant. 2002;11(6):513-8.	Anti-rat antilymphocyte serum	Intraperitoneal administration 0.5 ml	1 day after islet transplantation

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[1] E-mail: leandro.iuamoto@gmail.com