An association between a lymphocyte antigen in sheep and the response to vaccination against the parasite Trichostrongylus colubriformis

Lymphocyte antigens were tested in sheep which had been selected for responsiveness to vaccination against the intestinal nematode Trichostrongylus colubriformis. These sheep had been bred in an assortative mating programme which produced offspring designated as either “high responders” or “low responders”, with highly heritable resistance or susceptibility.Ovine lymphocyte antigen (OLA) typing antisera were obtained from parous ewes in the course of matings which produced the high and low responder flocks. A particular antigen (SY1) was found to be present in high frequency on the lymphocytes of high responder (72·2%) and in lower frequency (21·9%) on the lymphocytes of low responder rams. In ewes, the frequency for high responders was 65·7% and for low responders it was 33·5%. A similar association between the SY1 antigen and low faecal egg count was found in random-bred sheep which had been vaccinated with irradiated larvae and challenged with normal larvae. The conclusion was drawn that this lymphocyte antigen was likely to be part of the sheep major histocompatibility complex which influenced the immune response of sheep to vaccination against the parasite.     

The segregation of lambs into ‘responders’ and ‘non-responders’: Response to vaccination with irradiated Trichostrongylus colubriformis larvae before weaning

Random bred Merino ram and ewe lambs were vaccinated at 1, 2 and/or 3 months of age with irradiated T. colubriformis larvae. An exponentially increasing challenge of normal larvae was given to all groups including unvaccinated controls commencing at 1 month of age. The results, based on faecal egg counts, showed a dissociation into animals which responded to vaccination (geometric mean egg count 441) and those which did not (geometric mean egg count 1567). The proportion of responders was greatest in groups first vaccinated at the earliest age (1 month). Wool growth and liveweight gains showed severe depression corresponding to peak egg counts, however, responders were less affected than non-responders. There was no correlation between haemoglobin type and resistance to challenge. Faecal egg counts after impulse challenge with 10,000 normal larvae given at about 6$\text{1}\text{2}$ months of age showed a significant ranked correlation with those obtained during the primary exponential challenge. These results confirm that a proportion of young lambs respond to vaccination with irradiated larvae, and that genetically-determined factors are implicated in the ability of animals to respond to vaccination at an early age.     

The response of lambs to vaccination at weaning with irradiated Trichostrongylus colubriformis larvae: segregation into 'responders' and 'non-responders'

Dineen J. K., Gregg P. and Lascelles A. K. 1978. The response of lambs to vaccination at weaning with irradiated Trichostrongylus colubriformis larvae: segregation into ‘responders’ and ‘non-responders’. International Journal for Parasitology8: 59–63. Groups of colostrum fed and colostrum deprived lambs were vaccinated with irradiated Trichostrongylus colubriformis larvae at weaning (3 months) and challenged with normal infective larvae. As there was no significant difference between the worm counts of these groups after challenge, it was concluded that the failure of lambs, generally, to respond to vaccination as vigorously as mature sheep, was not due to ‘feed-back inhibition’ of the immune response by the action of maternal antibody.However the results showed that the lambs segregated into ‘responders’ and ‘non-responders’. The mean worm count of responders was 1560 whereas for non-responders this was 24,340. A responder was defined as an animal whose worm count was less than the lower limit of the 99 % confidence interval of unvaccinated controls. These results suggest that genetically-determined factors play an important role in the responsiveness of lambs to vaccination.Whereas counts of globule leucocytes in duodenal tissues were negatively correlated with worm counts (i.e. positively correlated with resistance), counts of both eosinophils and neutrophils were positively correlated with worm counts. These findings suggest that either globule leucocytes are involved in the resistance mechanism, or they are by-products of cellular events involved in resistance. On the other hand it is unlikely that either eosinophils or neutrophils are involved in the mechanism of resistance.     

B cells from Patients with Rheumatoid Arthritis Show Conserved CD39-Mediated Regulatory Function and increased CD39 Expression After Positive Response to Therapy

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by progressive joint destruction associated with increased pro-inflammatory mediators. In inflammatory microenvironments, exogenous ATP (eATP) is hydrolyzed to adenosine, which exerts immunosuppressive effects, by the consecutive action of the ectonucleotidases CD39 and CD73. Mature B cells constitutively express both ectonucleotidases, converting these cells to potential suppressors. Here, we assessed CD39 and CD73 expression on B cells from treated or untreated patients with RA. Neither the frequency of CD73⁺CD39⁺ and CD73^-CD39⁺ B cell subsets nor the levels of CD73 and CD39 expression on B cells from untreated or treated RA patients showed significant changes in comparison to healthy controls (HC). CpG+IL-2-stimulated B cells from HC or untreated RA patients increased their CD39 expression, and suppressed CD4⁺ and CD8⁺ T cell proliferation and intracellular TNF-production. A CD39 inhibitor significantly restored proliferation and TNF-producing capacity in CD4⁺ T cells, but not in CD8⁺ T cells, from HC and untreated RA patients, indicating that B cells from untreated RA patients conserved CD39-mediated regulatory function. Good responder patients to therapy (R-RA) exhibited an increased CD39 but not CD73 expression on B cells after treatment, while most of the non-responder (NR) patients showed a reduction in ectoenzyme expression. The positive changes of CD39 expression on B cells exhibited a negative correlation with disease activity and rheumatoid factor levels. Our results suggest modulating the ectoenzymes/ADO pathway as a potential therapy target for improving the course of RA.     

An approach to confirmatory testing of subpopulations in clinical trials

In oncology studies with immunotherapies, populations of “super‐responders” (patients in whom the treatment works particularly well) are often suspected to be related to biomarkers. In this paper, we explore various ways of confirmatory statistical hypothesis testing for joint inference on the subpopulation of putative “super‐responders” and the full study population. A model‐based testing framework is proposed, which allows to define, up‐front, the strength of evidence required from both full and subpopulations in terms of clinical efficacy. This framework is based on a two‐way analysis of variance (ANOVA) model with an interaction in combination with multiple comparison procedures. The ease of implementation of this model‐based approach is emphasized and details are provided for the practitioner who would like to adopt this approach. The discussion is exemplified by a hypothetical trial that uses an immune‐marker in oncology to define the subpopulation and tumor growth as the primary endpoint.     

The effect of acquired resistance on adult worms of Trichostrong ylus colubriformis in lambs

Dineen J. K. and Windon R. G. 1980. The effect of acquired resistance on adult worms of Trichostrongylus colubriformis in Lambs. International Journal for Parasitology10: 249–252. Wether lambs were classified as either responders or non-responders to vaccination and challenge with Trichostrongylus colubriformis. Worms recovered from these animals and unvaccinated controls were measured, eggs in utero counted and sex ratios (male/female) were determined for individual burdens. The results showed that all three parameters were reduced in responder lambs compared with non-responder and unvaccinated lambs and were positively correlated with worm counts in responder lambs whereas they tended to be negatively correlated with worm counts in non-responders and unvaccinated animals.These various effects of resistance on parasite development in responder lambs may be due to the action of endogenous inflammatory agents generated immunologically. On the other hand negative correlation between developmental parameters and worm burdens in non-responders and unvaccinated lambs suggests that development of parasites in heavy infections may be restricted by competition for a limiting physiological, spatial or nutritional resource of the host.     

Expression levels of genes for ATP-binding cassette transporters and sterol 27-hydroxylase in liver and intestine of baboons with high and low cholesterolemic responses to dietary lipids

Baboons with high and low lipemic responses to dietary lipids differ in intestinal cholesterol absorption and hepatic cholesterol metabolism. ATP-binding cassette (ABC) transporters play an important role in cholesterol absorption and hepatic cholesterol metabolism. Using frozen tissues from high- and low-responding baboons maintained on the cholesterol and fat-enriched diet, we determined the relative expression of ABCA1, ABCG5, ABCG8, and 27-hydroxylase genes in the liver and intestine using TaqMan real-time polymerase chain reaction. There was no consistent difference in the expression of ABC-transporters and 27-hydroxylase in the intestine between high- and low-responding baboons. However, hepatic expression of sterol 27-hydroxylase, ABCG5, and ABCG8 was higher in low-responding baboons than in high-responding baboons. There was also a significant correlation between the expression of sterol 27-hydroxylase and ABCG5, and ABCG8 in both the liver and the intestine. These results suggest that differences in hepatic lipid metabolism but not in cholesterol absorption between high- and low-responding baboons observed previously may be mediated by the differences in the expression levels of 27-hydroxylase, ABCG5, and ABCG8.