Table 1.

Summary of Successful and Unsuccessful Immunotherapy-Based Approaches in Type 1 Diabetes and Relevant Animal Models.

A. Successful Clinical Trials
Therapy	Efficacy in animal model	Comments	Principle adverse events	References
Cyclosporine A	+ NOD mouse, BB/W rat	Continued use of the drug was needed.	Renal toxicity	(Assan et al., 1994; Bougneres et al., 1988; Bougneres et al., 1990; Feutren et al., 1986; Laupacis et al., 1983; Mori et al., 1986; Stiller etal., 1984)
Antithymocyte globulin (alone or with prednisone)	+ NOD mouse with Exendin-4, not as single agent	Also part of a hematopoietic stem cell transplant protocol	Thrombocytopenia, serum sickness	(Eisenbarth et al., 1985; Ogawa et al., 2004; Saudek et al., 2004; Simon et al., 2008; Voltarelli et al., 2007)
Anti-CD3 mAb	+ NOD mouse	Late timing was an issue in the first report but not in a second report.	Mild transient cytokine release, Transient EBV reactivation.	(Chatenoud et al., 1997; Chatenoud et al., 1994; Herold et al., 1992; Herold et al., 2005; Herold et al., 2002; Keymeulen et al., 2005)
Rituximab	+ NOD mouse		Grade 1 or 2 infusion related reactions	(Hu et al., 2007; Pescovitz et al., 2009)
Etanercept	+NOD mouse but depending on timing: - for older mice	Pilot human trial	No significant drug related adverse events	(Jacob et al., 1990; Mastrandrea et al., 2009)
GAD65	+NOD mouse	Only in those with diabetes < 6mos duration	Mild site irritation, no significant drug related adverse events	(Agardh et al., 2005; Ludvigsson et al., 2008; Tian et al., 1996; Tisch et al., 1993)
Oral insulin (Prevention)	+ NOD mouse	Only a subset of pre-diabetic subjects with high IAA titer	No significant drug related adverse events	(Skyler et al., 2005; Zhang et al., 1991)
Closed loop insulin		A “biostator” (closed loopsystem) was used and suppressed endogenous insulin production. No immune therapy was given.	Hypoglycemia	(Shah et al., 1989)
B. Unsuccessful Clinical Trials
Nicotinamide	+ NOD mouse		No significant drug related adverse events	(Gale et al., 2004; Kolb and Burkart, 1999; O’Brien et al., 2000; Yamada et al., 1982)
Intranasal insulin	+NOD mouse		Nasal irritation and discharge, cough, fever, GI symptoms	(Bonifacio et al., 2008; Every etal., 2006; Harrison et al., 2004; Nanto- alonen et al., 2008)
Parenteral insulin	+ NOD mouse	A pilot clinical trial showed efficacy	Chemical hypoglycemia	(Atkinson et al., 1990; Diabetes Prevention Trial –Type 1 Diabetes Study Group, 2002)
Oral insulin	+ NOD mouse	See above. A change in the IAA titer for inclusion appeared to result in dilution of the drug effect.	No significant drug related adverse events	(Skyler et al., 2005; Zhang et al., 1991)
Insulin in incomplete Freund s adjuvant	+ NOD mouse	Small pilot trial, generated high titers of anti-insulin antibodies	No significant drug related adverse events	(Orban et al., 2009; Skyler etal., 2005; Zhang et al., 1991)