Human alpha 1-antitrypsin therapy induces fatal anaphylaxis in non-obese diabetic mice - PubMed (original) (raw)

Comparative Study

doi: 10.1111/j.1365-2249.2008.03721.x. Epub 2008 Aug 28.

M Parker, A Pileggi, B Zhang, Y-K Choi, R D Molano, C Wasserfall, C Ricordi, L Inverardi, M Brantly, D Schatz, M Atkinson, S Song

Affiliations

Comparative Study

Human alpha 1-antitrypsin therapy induces fatal anaphylaxis in non-obese diabetic mice

Y Lu et al. Clin Exp Immunol. 2008 Oct.

Abstract

Previous studies have shown that human alpha-1 antitrypsin (hAAT) gene delivery prevents type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. Furthermore, hAAT protein administration prolongs acceptance of islet allografts. Therefore, we evaluated the use of purified hAAT protein therapy to prevent T1D in NOD mice. Female NOD, non-obese resistant (NOR), Balb/c and C57BL/6 mice were injected intraperitoneally with vehicle alone or vehicle containing hAAT, human albumin or mouse albumin (or mg/injection/mouse; 2x/week). Preparations of clinical-grade hAAT included API(R), Aralast, Prolastin and Zemaira. Surprisingly, hAAT administration was associated with a high rate of fatal anaphylaxis. In studies seeking T1D prevention at 4 weeks of age, 100% mice died after six injections of hAAT. When administrated at 8-10 weeks of age, most (80-100%) NOD mice died following the fourth injection of hAAT, while 0% of Balb/c and C57BL/6 mice and 10% of NOR mice died. Interestingly, repeated injections of human albumin, but not mouse albumin, also induced sudden death in NOD mice. Antibodies to hAAT were induced 2-3 weeks after hAAT administration and death was prevented by treatment with anti-platelet-activating factor along with anti-histamine. In studies of disease reversal in NOD mice, using the four pharmaceutical grade formulations of hAAT, anaphylactic deaths were observed with all hAAT preparations. The propensity for fatal anaphylaxis following antigenic administration appears to be NOD- but not hAAT-specific. The susceptibility of NOD mice to hypersensitivity provides a significant limitation for testing of hAAT. Development of strategies to avoid this unwanted response is required to use this promising therapeutic agent for T1D.

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Figures

Fig. 1

Fig. 1

Fatal anaphylaxis in non-obese diabetic (NOD) mice receiving human alpha-1 antitrypsin (hAAT) (Prolastin®, 1 mg/mouse/injection, two injections/week). (a) Five-week-old female NOD mice (n = 26) were injected intraperitoneally (i.p.); (b) 10-week-old mice (n = 10) were injected i.p. Each bar represents the death rate of each injection. (c, d) Effect of two injections of hAAT (n = 6) or phosphate-buffered saline (n = 5) at 12 weeks of age. hAAT levels were monitored by enzyme-linked immunosorbent assay (ELISA) (c); serum anti-hAAT immunoglobulin E (IgE) levels detected by ELISA (d) Each line represents the average optical density at 50× dilution. *P < 5; **P < 1. (e) Treatment of anti-platelet-activating factor and anti-histamine prior to the fourth and fifth injections of hAAT prevented anaphylaxis. Each bar represents the survival rate after hAAT injection (n = 4).

Fig. 2

Fig. 2

Anaphylaxis is non-obese diabetic (NOD)-specific, but not human alpha-1 antitrypsin (hAAT)-specific. (a) Mortality rates in NOD, non-obese resistant and Balb/c mice (8 weeks of age) injected with hAAT (Prolastin® or Aralast®), human albumin (Albuminar®) or mouse albumin as indicated (n = 10, 2 mg/mouse, two injections per week); (b) anti-hAAT immunoglobulin G (IgG) levels. Each line represents the average optical density (OD) at 100× dilution; (c) anti-hAAT IgE levels. Each line represents the average OD at 50× dilution.

Fig. 3

Fig. 3

Blood glucose levels in alpha-1 antitrypsin (hAAT)-treated diabetic mice. New-onset diabetic mice were treated with insulin and hAAT (1 mg/mouse, two injections per week) from different manufacturers. (a) API® from Kamada; (b) Aralast® from Alpha Therapeutic Corp.; (c) Prolastin® from Bayer; (d) Zemaira® from Aventis; (e) Albuminar® from ZLB Behring; (f) saline as a control.

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