Timing of Cyclosporin-a Therapy for Abrogation of HVG and GVH Responses in Rats

Markwick, J.R.; Hobbs, J. R.; Chambers, JD; Pegrum, G. D.

doi:10.1016/s0140-6736(79)92441-3

Cited by 22 publications

(8 citation statements)

References 13 publications

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“…We believe adoption of the normal, surgically intact rat as an experimental model to investigate the toxicological properties of Cy A has facilitated clearer interpretation of the unwanted effects of this immune suppressant than would have been possible in transplant recipients. The amount of drug given in the present study (100 mg/kg/24 hr) is higher than the oral dose which has been found to produce significant immune suppression (Markwick et al, 1979;Denham et al, 1980;Homan et al, 1980) with only minor impairment of hepatic and renal function in this species (Whiting et al, 1980;Thomson et al, 1981b). It is, however, considerably in excess of the initial dose (17 mg/kg/24 hr) currently administered to human renal transplant patients (Calne et al,198 1).…”

Section: Discussionmentioning

confidence: 62%

Toxicity of the immune suppressant cyclosporin A in the rat

Blair

Thomson

Whiting

et al. 1982

The Journal of Pathology

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Cyclosporin A (Cy A) administered orally (100 mg/kg/24 hr) to adult Sprague‐Dawley rats for 21 days caused a number of functional and structural changes. Behavioural effects, including fits, were also observed during the first week. Two animals (25 per cent.) died on days 6 and 10 respectively; a third was killed on day 7 because of fits. Hair loss was continuous during the experimental period. There were marked decreases in total serum protein, albumin and aspartate aminotransferase, accompanied by rises in alkaline phosphatase and total bilirubin. Examination of the liver revealed moderate centrilobular fatty change and minor dilatation of endoplasmic reticulum. Impaired renal function was also evident from increases in serum urea and creatinine and a striking rise in urinary N‐acetyl‐β‐D‐glucos‐aminidase activity. Kidneys examined at 21 days showed focal proximal tubular cell (PTC) vacuolation and necrosis, clearly evident on light microscopy. Ultrastructural studies revealed dilatation and vesiculation of the smooth endoplasmic reticulum within PTC, together with increased lysosome production and the formation of myeloid figures. Glomeruli and distal tubular cells were unaffected. Cy A caused marked lymphopenia, with a progressive increase in circulating neutrophils and monocytes. This was accompanied by the appearance of atypical mononuclear cells in the peripheral blood. The cellularity of the bone marrow was significantly reduced. In the thymus, there was very marked depletion of the medullary zones, and histiocytes containing cellular debris appeared throughout. The most striking feature in the spleen was the loss of lymphocytes within the periarteriolar sheaths and marginal zones.

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Section: Discussionmentioning

confidence: 62%

Toxicity of the immune suppressant cyclosporin A in the rat

Blair

Thomson

Whiting

et al. 1982

The Journal of Pathology

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“…To investigate the population of T-cells responsible for resistance to B. pahangi infection, rats were treated with the immunosuppressive drug cyclosporin A. Fifteen PVG rats were inoculated with 100 L3 each and 7 of these treated with CsA at 25 mg/kg for 5 days a week, starting from day 1 p.i. This dose was chosen since it produces significant immune suppression in rats (Markwick et al 1979). Mf were counted at intervals and adult worms were counted at autopsy 100 days p.i.…”

Section: Effects Of Csa Upon B Pahangz Infection In Ratsmentioning

confidence: 99%

Brugia pahangi infections in immune‐compromised rats demonstrate that separate mechanisms control adult worm and microfilarial numbers

Lawrence

Denham

1992

Parasite Immunology

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The immunological basis of resistance to Brugia pahangi infection in rats was studied. Infections were investigated in athymic rnu/rnu rats and in rats treated with the immuno-suppressive agents cyclosporin A (CsA) or cyclophosphamide (Cy). The recovery of adult worms in normal rats was 1-2% in comparison to 12.2% recovery in athymic rats. CsA and Cy treated rats did not have increased adult worm burdens. Microfilarial (Mf) levels (expressed as Mf per ml per adult worm) were highly elevated in both athymic and Cy treated rats but not in CsA treated rats. IgG and IgM levels to B. pahangi antigens were severely depressed in both athymic and Cy treated rats. IgG levels but not IgM levels were abrogated in CsA treated rats. These results implied that control of larval establishment or adult killing, and regulation of Mf levels are separate T-cell dependent mechanisms and act independently of IgG antibody. Control of Mf levels is associated with a specific IgM response which is Cy sensitive but CsA resistant.

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“…In the group overall, 6 out of 13 died before their grafts were rejected ( Table 2), though one was killed for reasons that could not be related to the drug. The 5 deaths (42-6%) occurred on days 14,15,27,35, and 83 among animals receiving both high (2 rabbits) and low (3 rabbits) dosages. The greater death rate in this group compared with controls and topically treated groups was significant (0-05>p>001, t test).…”

Section: Effect Of Corneal Revascularisation On Graft Survivalmentioning

confidence: 99%

Corneal graft rejection: a new rabbit model and cyclosporin-A.

Hunter¹,

Garner²,

Wilhelmus³

et al. 1982

British Journal of Ophthalmology

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In order to test the efficacy of topically applied cyclosporin-A in preventing corneal allograft rejection, existing rabbit models were modified to produce a new model in which the allograft reaction could be consistently initiated solely as a result of corneal transfer without any additional means of sensitisation. With this model, which reflects clinical corneal grafting more closely than many previous models, cyclosporin-A 1% drops applied to the recipient eye 5 times daily for 4 weeks inhibited corneal graft rejection. When cyclosporin-A 1% drops were applied to corneal allografts for 13 weeks, 44% of grafts remained clear 180 days after transplantation. No side effects were observed that could be attributed to topically applied cyclosporin-A.

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Timing of Cyclosporin-a Therapy for Abrogation of HVG and GVH Responses in Rats

Cited by 22 publications

References 13 publications

Toxicity of the immune suppressant cyclosporin A in the rat

Toxicity of the immune suppressant cyclosporin A in the rat

Brugia pahangi infections in immune‐compromised rats demonstrate that separate mechanisms control adult worm and microfilarial numbers

Corneal graft rejection: a new rabbit model and cyclosporin-A.

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