AGRICULTURAL EXPERIMENTS AND THEIR ECONOMIC SIGNIFICANCE (II) and DISCUSSION

This paper discusses what economists want experimenters to do, and why, and criticises existing methods from the economists' viewpoint. The subject has received very little serious attention outside of North America and practically none, as far as I am aware, in Australia. The exception is a valuable critical survey, by Pearse, of the Department of Agriculture's experimental work in a large part of Western Australia. We are concerned in this paper only with certain types of agricultural experiments; namely (i) experiments which investigate physical input-output relationships (such as fertiliser, feeding and stocking rates) and (ii) where the technical data alone does not suffice to indicate an optimum

CD27 costimulation contributes substantially to the expansion of functional memory CD8+ T cells after peptide immunization

Naive T cells require signals from multiple costimulatory receptors to acquire full effector function and differentiate to long-lived memory cells. The costimulatory receptor, CD27, is essential for optimal T-cell priming and memory differentiation in a variety of settings although whether CD27 is similarly required during memory CD8+ T-cell re-activation remains controversial. We have used OVA and anti-CD40 to establish a memory CD8+ T-cell population and report here that their secondary expansion, driven by peptide and anti-CD40, polyI:C or LPS requires CD27. Furthermore, antigenic peptide and a soluble form of the CD27 ligand, CD70 (sCD70), is sufficient for secondary memory CD8+ T-cell accumulation at multiple anatomical sites, dependent on CD80/86. Prior to boost, resting effector- and central-memory CD8+ T cells both expressed CD27 with greater expression on central memory cells. Nonetheless both populations upregulated CD27 after TCR engagement and accumulated in proportion after boosting with antigen and sCD70. Mechanistically, sCD70 increased the frequency of divided and cytolytic memory T cells, conferred resistance to apoptosis and enabled retardation of tumor growth in vivo. These data demonstrate the central role played by CD27/70 during secondary CD8+ T-cell activation to a peptide antigen, and identify sCD70 as an immunotherapeutic adjuvant for anti-tumor immunit

Augmentation of CD134 (OX40)-dependent NK anti-tumour activity is dependent on antibody crosslinking

CD134 (OX40) is a member of the tumour necrosis factor receptor superfamily (TNFRSF). It acts as a costimulatory receptor on T cells, but its role on NK cells is poorly understood. CD137, another TNFRSF member has been shown to enhance the anti-tumour activity of NK cells in various malignancies. Here, we examine the expression and function of CD134 on human and mouse NK cells in B-cell lymphoma. CD134 was transiently upregulated upon activation of NK cells in both species. In contrast to CD137, induction of CD134 on human NK cells was dependent on close proximity to, or cell-to-cell contact with, monocytes or T cells. Stimulation with an agonistic anti-CD134 mAb but not CD134 ligand, increased IFNγ production and cytotoxicity of human NK cells, but this was dependent on simultaneous antibody:Fcγ receptor binding. In complementary murine studies, intravenous inoculation with BCL1 lymphoma into immunocompetent syngeneic mice resulted in transient upregulation of CD134 on NK cells. Combination treatment with anti-CD20 and anti-CD134 mAb produced a synergistic effect with durable remissions. This therapeutic benefit was abrogated by NK cell depletion and in Fcγ chain −/− mice. Hence, anti-CD134 agonists may enhance NK-mediated anti-tumour activity in an Fcγ receptor dependent fashion

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 1 Historical and established therapies

Multiple sclerosis (MS) is a potentially life-changing immune mediated disease of the central nervous system. Until recently, treatment has been largely confined to acute treatment of relapses, symptomatic therapies and rehabilitation. Through persistent efforts of dedicated physicians and scientists around the globe for 160 years, a number of therapies that have an impact on the long term outcome of the disease have emerged over the past 20 years. In this three part series we review the practicalities, benefits and potential hazards of each of the currently available and emerging treatment options for MS. We pay particular attention to ways of abrogating the risks of these therapies and provide advice on the most appropriate indications for using individual therapies. In Part 1 we review the history of the development of MS therapies and its connection with the underlying immunobiology of the disease. The established therapies for MS are reviewed in detail and their current availability and indications in Australia and New Zealand are summarised. We examine the evidence to support their use in the treatment of MS

A new era in the treatment of multiple sclerosis

• Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. • A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. • While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. • The importance of early treatment in minimising long-term disability is increasingly recognised. • Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. • While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects

Antibodies to costimulatory receptor 4-1BB enhance anti-tumor immunity via T regulatory cell depletion and promotion of CD8 T cell effector function

The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcγR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells, followed by either agonistic anti-4-1BB IgG1 or anti-PD-1 mAb augmented anti-tumor responses in multiple solid tumor models. An antibody engineered to optimize both FcγR-dependent Treg cell depleting capacity and FcγR-independent agonism delivered enhanced anti-tumor therapy. These insights into the effector mechanisms of anti-4-1BB mAbs lay the groundwork for translation into the clinic. Buchan et al. reveal dual anti-tumor activities for antibodies to the co-stimulatory receptor 4-1BB, which depend on antibody isotype and FcγR availability. Sequential scheduling of anti-4-1BB and checkpoint blockade mAbs, and antibodies engineered to harness both Treg cell depleting and effector cell agonism properties show potent anti-tumor activity in preclinical models, laying the groundwork for translation into the clinic