Effect of BLV Infection on the Immune Function of Polymorphonuclear Neutrophil in Dairy Cows

Enzootic bovine leukemia is a late-onset, neoplastic infection caused by the bovine leukemia virus (BLV). BLV infection hinders the function of the immune system and induces other diseases, which negatively affects the performance and health of the infected cows. As the first line of defense against invading foreign pathogenic microorganisms, polymorphonuclear neutrophil (PMN) plays a vital role in the immune system of dairy cows. However, research on the effect of BLV infection on the immune function of PMN in dairy cows is scarce. Therefore, this experiment aimed to elucidate the effects and effect mechanisms of BLV infection on the immune function of PMN in dairy cows with different BLV provirus loads by detecting the chemotaxis, migration, adhesion, phagocytosis, respiratory burst function, and the formation of NETs. The experimental results showed that BLV infection had no significant effect on the phagocytosis of PMN but inhibited their migration and respiratory burst function, and the effects were closely related to the BLV provirus load. Under high BLV provirus load, PMN produced large amounts of NETs, chemokine CXCL7, adhesion molecule CD18, and pro-inflammatory factors IL-8 and TNF-α, triggering inflammatory responses, and tissue damage. The results of this study will help reveal the reason why BLV infection causes the high incidence of mammary gland inflammation in dairy cows.

Cytotoxic T-Lymphocyte Analysis of Aggressive Types of Adult T-Cell Leukemia/Lymphoma Patients with Complete Remission after Intensive Combination Chemotherapy

Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-I). Most ATLL cells are CD4 and CCR4 positive, and CD8 negative. ATLL is classified into 4 clinical subtypes: smoldering, chronic, acute, and lymphoma. Acute and lymphoma type ATLLs, which are aggressive types, have a very poor prognosis. In Japan, aggressive ATLLs are commonly treated by intensive chemotherapies, such as VCAP-AMP-VECP, modified LSG15 therapy, and biweekly CHOP therapy. Recently, an anti-CCR4 monoclonal antibody (mogamulizumab) was approved for relapse and refractory ATLL in Japan. Mogamulizumab induces a highly potent antibody dependent cellular cytotoxicity, suggesting the importance of immuno-cell therapy for treatment of ATLL. We report here the extremely interesting results of aggressive ATLL patients with long-term survival and complete remission (CR) after activation of cellular immunity against ATLL cells following intensive chemotherapies. Patients and Methods: We retrospectively evaluated 46 cases of aggressive ATLLs diagnosed at the Nagasaki Genbaku Hospital between January 2001 and August 2011. Of these, 7 patients had long-term survival greater than 3 years with CR after intensive chemotherapies. Four of these 7 patients had human leukocyte antigen (HLA)-A02:01 or HLA-A24:02, and were investigated using anti-HTLV-I specific cytotoxic T-lymphocyte (CTL) analysis. The HTLV-I provirus load in peripheral blood was also analyzed. Results: Table 1 summarizes the characteristics of 7 aggressive type ATLL patients with long-term survival. Four patients were male and 3 were female. Six patients were classified as lymphoma type and 1 as acute type ATLL. The median age was 68 (range, 60–78) years. The median survival period from the onset of the disease was 111 (range, 36–165) months. In all 7 patients, the CD4/CD8 ratio reversed during, or shortly after, chemotherapy and CD8 predominance continued for more than 1 year (range, 13–165 months, median 24 months). Three patients had herpes virus infection during chemotherapy and reversal of the CD4/CD8 ratio appeared just after herpes virus infection in 2 of these patients. These observations suggested that HTLV-I specific CTLs were induced and contributed to the treatment of ATLL in these patients. An HTLV-I specific CTL analysis currently is available in patients with HLA-A02:01 and HLA-A24:02. Three of 7 aggressive ATLL patients with long-term survival and CR had HLA-A02:01 and 1 had HLA-A24:02. Therefore, HTLV-I specific CTL analysis and HTLV-I provirus load in the peripheral blood were performed in all 4 patients. Each patient was examined twice, once in 2012 and once in 2014. HTLV-I specific CTLs were detected in all patients (Table 2 and Figure 1). Although all patients maintained CR for, HTLV-I proviruses were detected in the peripheral blood in all patients (Table 2). This phenomenon was observed both in 2012 and in 2014 (Table 2 and Figure 1). Conclusions: The findings from this study suggest that HTLV-I specific CTLs can be induced in patients with aggressive types of ATLL. In patients having long survival with CR, these CTLs can contribute to treatment and may play a roll inhibiting the relapse of ATLL. The development of efficacious methods to induce HTLV-I specific CTLs in individual ATLL patients may lead to improved outcomes for aggressive types of ATLL. Table 1. Summary of aggressive type ATLL patients with long-term survival and complete remission PatientNo. Gender Age(year) Survival fromthe onset of ATLL (months) Duration ofCD4/CD8 reversal(months) Herpes virus infection 1 Male 69 165 165 + 2 Male 68 140 96 + 3 Female 71 71 65 - 4 Male 60 124 13 + 5 Female 61 111 18 - 6 Male 78 36 13 - 7 Female 65 56 24 - Table 2. A Summary of HTLV-I specific CTL analysis and HTLV-I provirus load in the peripheral blood Patient No. HLA 2012 2014 CTL HTLV-I provirus CTL HTLV-I provirus (%) (copies/1000 cells) (%) (copies/1000 cells) 1 A02:01 0.11 35.4 0.13 61.9 2 A02:01 0.78 24.4 1.56 14.7 5 A02:01 1.06 7.1 1.31 13.3 7 A24:02 2.07 26.4 3.64 27.9 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Differences in viral and host genetic risk factors for development of human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis between Iranian and Japanese HTLV-1-infected individuals

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disease observed only in 1–2 % of infected individuals. HTLV-1 provirus load, certain HLA alleles and HTLV-1 tax subgroups are reported to be associated with different levels of risk for HAM/TSP in Kagoshima, Japan. Here, it was determined whether these risk factors were also valid for HTLV-1-infected individuals in Mashhad in northeastern Iran, another region of endemic HTLV-1 infection. In Iranian HTLV-1-infected individuals (n=132, 58 HAM/TSP patients and 74 seropositive asymptomatic carriers), although HLA-DRB1*0101 was associated with disease susceptibility in the absence of HLA-A*02 (P=0·038; odds ratio=2·71) as observed in Kagoshima, HLA-A*02 and HLA-Cw*08 had no effect on either the risk of developing HAM/TSP or HTLV-1 provirus load. All Iranian subjects possessed tax subgroup A sequences, and the protective effects of HLA-A*02 were observed only in Kagoshima subjects with tax subgroup B but not in those with tax subgroup A. Both the prevalence of HTLV-1 subgroups and the host genetic background may explain the different risks levels for HAM/TSP development in these two populations.