Intralesional lipid-complexed cytokine/superantigen immunogene therapy for spontaneous canine tumors

These studies sought to determine the gene expression and short-term effects of intralesional lipid-complexed immunogene therapy with constructs encoding Staphylococcus aureus enterotoxin A and canine interleukin-2 (L-SEA/cIL-2) in dogs with tumors of various histotypes, and then to assess the safety and efficacy of repeated L-SEA/cIL-2 injections in dogs with spontaneous soft tissue sarcomas (STS). In the first study, pet dogs with a variety of tumors received a single intralesional injection of L-SEA/cIL-2, and surgical excision was performed 48 h later. In the second study, dogs with histologically confirmed STS were treated weekly for a maximum of 12 weeks with escalating doses of L-SEA/cIL-2. Tumors were then surgically excised and assessed histologically and immunohistochemically. Overall, treatments were well tolerated, with no dose-limiting toxicities encountered. At 48 h, in the single injection study, plasmid DNA was detected in 14 of 16 tumor samples, and plasmid-specific mRNA was detected in 3 of 14. In the multiple injection study, the overall response rate in dogs with STS was 25%, consisting of 3 complete responses (CR) and 1 partial response (PR). Diffuse lymphoplasmacytic inflammation was observed in all tumors from patients experiencing CR or PR, whereas these changes were not evident in tumors from nonresponders. The infiltrate was composed primarily of CD3(+) cells at 48 h from the single-injection study, and was composed of both CD3(+) and CD79a(+) cells at 12 weeks in responding dogs from the multiple-injection study. In conclusion, these studies suggests that intralesional L-SEA/cIL-2 immunotherapy is well tolerated, results in detectable transgene expression in canine tumors, and has antitumor activity in dogs with spontaneous STS.     

Efficacy of domperidone gel in an induced model of fescue toxicosis in periparturient mares

The objective was to evaluate the efficacy of domperidone in the prevention of reproductive complications of fescue toxicosis in periparturient mares. Pregnant mares at ≤310 days of gestation were fed ≥200 μg ergovaline per kg diet daily in endophyte-infected fescue hay and seed, starting ≥30 days before their expected foaling date (EFD: 340 days after breeding). Thirty-five mares were randomized to a treatment group to receive either domperidone gel (n = 20, 1.1 mg/kg, PO, once daily) or placebo (n = 15). Treatment was initiated 10 to 15 days before the EFD and continued for 5 days after foaling. “Treatment success” was defined as foaling within 14 days of the EFD, adequate mammary development on the day of foaling, and adequate lactation for 5 days postpartum. Twenty-seven mares were included in the effectiveness analysis. More mares in the domperidone group (12/13, P < 0.0001) were treatment successes than in the control group (1/14). Gestation length was shorter (P = 0.0011), and lactation at foaling (P = 0.0011) was better for the domperidone-group mares. Foals from two control mares were born dead and four others died or were euthanized within a few days after birth, compared with one foal death (an autolyzed twin) from a domperidone-treated mare. Plasma IgG concentrations were evaluated in 24 foals. Failure of passive transfer of immunoglobulins (IgG <800 mg/dL) occurred in 13/16 (81%) foals of domperidone-group mares and 7/8 (88%) foals of control mares. In conclusion, the reproductive complications of fescue toxicosis in periparturient mares induced by a fescue seed/hay model were prevented by treatment with domperidone.     

Experimental Dirofilaria immitis-associated glomerulonephritis induced in part by in situ formation of immune complexes in the glomerular capillary wall

Eight dogs were immunized with an aqueous-soluble extract of adult Dirofilaria immitis. Subsequent to at least 7-fold increases in antibody titer, the left renal artery of each dog was infused with 6 mg of D. immitis antigen. Fourteen days after infusion, the left kidney was compared to the right kidney and preinfusion biopsies. All dogs developed glomerular lesions in the left kidney characterized by 1 or more of the following: mesangial cell proliferation, neutrophil infiltration, increased periodic acid-Schiff-positive staining of the mesangium and glomerular basement membrane (GBM), fibrin deposition, and thickening of the GBM. Left kidney glomerular immunofluorescence was positive in 7 of the 8 dogs using polyclonal antisera for canine IgG and C3 in a linear or fine granular pattern. Ultrastructural lesions were present in the left kidney of all dogs and consisted of irregular GBM thickening, intramembranous and mesangial electron-dense deposits, and mesangial and endothelial cell proliferation. Antibodies directed against D. immitis antigen were demonstrated in all kidney eluates from the left kidney. The right kidneys of 3 of the dogs developed lesions; however, in comparison to the left kidney, the lesions in the right kidneys were inconsistent, mild, and focal. The histologic findings in the left kidney were similar to those observed in dogs with naturally occurring D. immitis infections. In sham-immunized control dogs, renal arterial infusion of D. immitis antigen did not cause consistent immune complex glomerulonephritis; however, antigen adherence to glomerular capillary walls was observed by immunofluorescent microscopy.(ABSTRACT TRUNCATED AT 250 WORDS)