A Conceptual Analysis

Johne’s disease (JD) is a chronic, production-limiting disease of ruminants. Control programs aiming to minimize the effects of the disease on the dairy industry have been launched in many countries, including Canada. Those programs commonly focus on strict hygiene and management improvement, often combined with various testing methods. Concurrently, organic dairy farming has been increasing in popularity. Because organic farming promotes traditional management practices, it has been proposed that organic dairy production regulations might interfere with implementation of JD control strategies. However, it is currently unclear how organic farming would change the risk for JD control. This review presents a brief introduction to organic dairy farming in Canada, JD, and the Canadian JD control programs. Subsequently, organic practices are described and hypotheses of their effects on JD transmission are developed. Empirical research is needed, not only to provide scientific evidence for organic producers, but also for smaller conventional farms employing organic-like management practices

High endothelial venules are rare in colorectal cancers but accumulate in extra-tumoral areas with disease progression

Prolonged patient survival after surgical resection, is associated with a higher cytotoxic and memory T cell density within colorectal cancers (CRC). High endothelial venules (HEVs) are specialized blood vessels present in secondary lymphoid organs (SLO) that allow ingress of naïve and central memory T cells from the blood. It has been proposed that HEVs in tumors might serve as a similar route of entry for lymphocytes into the tumor and result in an improved prognosis. The present study aimed to characterize HEVs and their microenvironment in resected tumors from colorectal cancer patients (n = 62). We observed HEVs in association with lymphoid aggregates in 49 out of 62 patients. However, these HEV+ lymphoid aggregates were largely at the invasive margin of the tumor and although there was an association with lymphocytes and HEVs at the invasive margin (p = 0.002) there was only a very weak association with tumor infiltrating lymphocytes. Indeed, lymphoid aggregates were associated with more advanced disease (Dukes’ stage C) and did not indicate a favorable prognosis

A distinct chemokine axis does not account for enrichment of Foxp3+ CD4+T cells in carcinogen-induced fibrosarcomas

The frequency of CD4+ Foxp3+ regulatory T (Treg) cells is often significantly increased in the blood of tumour-bearing mice and people with cancer. Moreover, Treg cell frequencies are often higher in tumours compared with blood and lymphoid organs. We wished to determine whether certain chemokines expressed within the tumour mass selectively recruit Treg cells, thereby contributing to their enrichment within the tumourinfiltrating lymphocyte pool. To achieve this goal, the chemokine profile of carcinogen-induced fibrosarcomas was determined, and the chemokine receptor expression profiles of both CD4+ Foxp3 � and CD4+ Foxp3+ T cells were compared. These analyses revealed that the tumours are characterized by expression of inflammatory chemokines (CCL2, CCL5, CCL7, CCL8, CCL12, CXCL9, CXCL10 and CX3CL1), reflected by an enrichment of activated Foxp3 � and Foxp3+ T cells expressing T helper type 1- associated chemokine receptors. Notably, we found that CXCR3+ T cells were significantly enriched in the tumours although curiously we found no evidence that CXCR3 was required for their recruitment. Instead, CXCR3 marks a population of activated Foxp3 � and Foxp3+ T cells, which use multiple and overlapping ligand receptor pairs to guide their migration to tumours. Collectively, these data indicate that enrichment of Foxp3+ cells in tumours characterized by expression of inflammatory chemokines, does not occur via a distinct chemokine axis, thus selective chemokine blockade is unlikely to represent a meaningful therapeutic strategy for preventing Treg cell accumulation in tumours

Primary breast tumours but not lung metastases induce protective anti-tumour immune responses after Treg-depletion

Although metastatic disease is responsible for the majority of cancer deaths, tests of novel immunotherapies in mouse tumour models often focus on primary tumours without determining whether these therapies also target metastatic disease. This study examined the impact of depleting Foxp3+ regulatory T cells (Treg), on lung metastases, using a mouse model of breast cancer. After Treg-depletion, generation of an immune response to the primary tumour was a critical determinant for limiting development of metastasis. Indeed, resection of the primary tumour abrogated any effect of Treg-depletion on metastases. In addition, whilst the immune response, generated by the primary tumour, prevented metastases development, it had little impact on controlling established disease. Collectively, the data indicate that metastatic cells in the lung are not controlled by immune responses induced by the primary tumour. These findings indicate that targeting Tregs alone will not suffice for treating lung metastases

Induction and Exhaustion of Lymphocytic Choriomeningitis Virus–specific Cytotoxic T Lymphocytes Visualized Using Soluble Tetrameric Major Histocompatibility Complex Class I–Peptide Complexes

This study describes the construction of soluble major histocompatibility complexes consisting of the mouse class I molecule, H-2Db, chemically biotinylated β2 microglobulin and a peptide epitope derived from the glycoprotein (GP; amino acids 33–41) of lymphocytic choriomeningitis virus (LCMV). Tetrameric class I complexes, which were produced by mixing the class I complexes with phycoerythrin-labeled neutravidin, permitted direct analysis of virus-specific cytotoxic T lymphocytes (CTLs) by flow cytometry. This technique was validated by (a) staining CD8+ cells in the spleens of transgenic mice that express a T cell receptor (TCR) specific for H-2Db in association with peptide GP33–41, and (b) by staining virus-specific CTLs in the cerebrospinal fluid of C57BL/6 (B6) mice that had been infected intracranially with LCMV-DOCILE. Staining of spleen cells isolated from B6 mice revealed that up to 40% of CD8+ T cells were GP33 tetramer+ during the initial phase of LCMV infection. In contrast, GP33 tetramers did not stain CD8+ T cells isolated from the spleens of B6 mice that had been infected 2 mo previously with LCMV above the background levels found in naive mice. The fate of virus-specific CTLs was analyzed during the acute phase of infection in mice challenged both intracranially and intravenously with a high or low dose of LCMV-DOCILE. The results of the study show that the outcome of infection by LCMV is determined by antigen load alone. Furthermore, the data indicate that deletion of virus-specific CTLs in the presence of excessive antigen is preceded by TCR downregulation and is dependent upon perforin

Treg depletion licenses T cell-driven HEV neogenesis and promotes tumor destruction

T-cell infiltration into tumors represents a critical bottleneck for immune-mediated control of cancer. We previously showed that this bottleneck can be overcome by depleting immunosuppressive Foxp3+ regulatory T cells (Tregs), a process which can increase frequencies of tumor-infiltrating lymphocytes (TILs) through promoting development of specialized portals for lymphocyte entry, namely high endothelial venules (HEVs). In this paper, we used a carcinogen-induced tumor model, that allows for co-evolution of the tumor microenvironment and the immune response, to demonstrate that Treg depletion not only results in widespread disruption to HEV networks in lymph nodes (LNs) but activates CD8+ T cells, which then drive intratumoral HEV development. Formation of these vessels contrasts with ontogenic HEV development in LNs in that the process is dependent on TNF receptor and independent of lymphotoxin beta receptor-mediated signaling. These intratumoral HEVs do not express the chemokine CCL21, revealing a previously undescribed intratumoral blood vessel phenotype. We propose a model whereby Treg depletion enables a self-amplifying loop of T-cell activation, which promotes HEV development, T-cell infiltration, and ultimately, tumor destruction. The findings point to a need to test for HEV development as part of ongoing clinical studies in patients with cancer

Developing Strategies To Reduce Mastitis Caused By Environmental Streptococci

Godkin, Ann. (1998). Developing Strategies To Reduce Mastitis Caused By Environmental Streptococci. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/117326