Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice.
OBJECTIVE
Interruption of IL-2 signalling is an attractive therapeutic target in autoimmune disorders. In this study we evaluated the effect of a fusion protein composed of IL-2 and caspase-3 (IL2-cas) on NOD mice, as compared with disease induction by cyclophosphamide.


METHODS
IL2-cas was assessed in NOD mice at various ages and in conjunction with cyclophosphamide administration. The effect of IL2-cas on diabetogenic cells was evaluated in adoptive transfer experiments and in cell suspension in vitro.


RESULTS
IL2-cas induced apoptosis in T cells expressing the alpha chain of the IL-2 receptor (cluster of differentiation [CD]25) in vitro, with superior survival of T cells expressing CD4 and forkhead box P3 (FOXP3). The fusion protein decreased mixed lymphocyte reactivity, and pretreatment with IL2-cas decreased the efficacy of adoptive transfer of diabetes into NOD severe combined immunodeficiency mice. Administration of one dose of IL2-cas decreased the incidence of diabetes in NOD mice, showing a superior beneficial effect when administered at young age, and effectively blocked induction of hyperglycaemia by cyclophosphamide, reducing the severity of islet inflammation. Administration of IL2-cas caused an acute increase in CD25(-)FOXP3(+) T cells in the lymph nodes, pancreas and thymus in NOD mice, with similar effects in wild-type mice. Administration of IL2-cas after onset of hyperglycaemia resulted in superior survival.


CONCLUSIONS
Targeted elimination of cells expressing the IL-2 receptor by this fusion protein disrupts the autoimmune pathogenesis in prediabetic and diabetic NOD mice, despite depletion of CD25(+) regulatory T cells. Furthermore, this particular fusion protein is permissive to the development of FOXP3(+) T cells that might contribute to protracted protection from the progression of insulitis and overt hyperglycaemia.
Yarkoni
S
S
GASR Biotechnology, Kfar-Saba 44395, Israel.
Kaminitz
A
A
Sagiv
Y
Y
Askenasy
N
N
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D053148:Caspase 3 / Q000502:physiology*; D002455:Cell Division; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000503:physiopathology*; D007376:Interleukin-2 / Q000502:physiology; D053645:Interleukin-2 Receptor alpha Subunit / Q000172:deficiency / Q000276:immunology / Q000502:physiology; D008198:Lymph Nodes / Q000166:cytology / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000502:physiology; D011236:Prediabetic State / Q000276:immunology / Q000503:physiopathology*; D015375:Receptors, Interleukin-2 / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D053148:Caspase 3