Immune control of HIV-1 infection after therapy interruption: immediate versus deferred antiretroviral therapy

Abstract Background The optimal stage for initiating antiretroviral therapies in HIV-1 bearing patients is still a matter of debate. Methods We present computer simulations of HIV-1 infection aimed at identifying the pro et contra of immediate as compared to deferred Highly Active Antiretroviral Therapy (HAART). Results Our simulations highlight that a prompt specific CD8+ cytotoxic T lymphocytes response is detected when therapy is delayed. Compared to very early initiation of HAART, in deferred treated patients CD8+ T cells manage to mediate the decline of viremia in a shorter time and, at interruption of therapy, the virus experiences a stronger immune pressure. We also observe, however, that the immunological effects of the therapy fade with time in both therapeutic regimens. Thus, within one year from discontinuation, viral burden recovers to the value at which it would level off in the absence of therapy. In summary, simulations show that immediate therapy does not prolong the disease-free period and does not confer a survival benefit when compared to treatment started during the chronic infection phase. Conclusion Our conclusion is that, since there is no therapy to date that guarantees life-long protection, deferral of therapy should be preferred in order to minimize the risk of adverse effects, the occurrence of drug resistances and the costs of treatment.</p

Tertiary Lymphoid Structures in Cancer: Drivers of Antitumor immunity, immunosuppression, or Bystander Sentinels in Disease?

Secondary lymphoid organs are integral to initiation and execution of adaptive immune responses. These organs provide a setting for interactions between antigen-specific lymphocytes and antigen-presenting cells recruited from local infected or inflamed tissues. Secondary lymphoid organs develop as a part of a genetically preprogrammed process during embryogenesis. However, organogenesis of secondary lymphoid tissues can also be recapitulated in adulthood during de novo lymphoid neogenesis of tertiary lymphoid structures (TLSs). These ectopic lymphoid-like structures form in the inflamed tissues afflicted by various pathological conditions, including cancer, autoimmunity, infection, or allograft rejection. Studies are beginning to shed light on the function of such structures in different disease settings, raising important questions regarding their contribution to progression or resolution of disease. Data show an association between the tumor-associated TLSs and a favorable prognosis in various types of human cancer, attracting the speculation that TLSs support effective local antitumor immune responses. However, definitive evidence for the role for TLSs in fostering immune responses in vivo are lacking, with current data remaining largely correlative by nature. In fact, some more recent studies have even demonstrated an immunosuppressive, tumor-promoting role for cancer-associated TLSs. In this review, we will discuss what is known about the development of cancer-associated TLSs and the current understanding of their potential role in the antitumor immune response

Stromal Fibroblasts in Tertiary Lymphoid Structures: A Novel Target in Chronic Inflammation.

Tertiary lymphoid structures (TLS) are organized aggregates of lymphocytes, myeloid, and stromal cells that provide ectopic hubs for acquired immune responses. TLS share phenotypical and functional features with secondary lymphoid organs (SLO); however, they require persistent inflammatory signals to arise and are often observed at target sites of autoimmune disease, chronic infection, cancer, and organ transplantation. Over the past 10 years, important progress has been made in our understanding of the role of stromal fibroblasts in SLO development, organization, and function. A complex and stereotyped series of events regulate fibroblast differentiation from embryonic life in SLOs to lymphoid organ architecture observed in adults. In contrast, TLS-associated fibroblasts differentiate from postnatal, locally activated mesenchyme, predominantly in settings of inflammation and persistent antigen presentation. Therefore, there are critical differences in the cellular and molecular requirements that regulate SLO versus TLS development that ultimately impact on stromal and hematopoietic cell function. These differences may contribute to the pathogenic nature of TLS in the context of chronic inflammation and malignant transformation and offer a window of opportunity for therapeutic interventions in TLS associated pathologies

Tertiary Lymphoid Structures:Autoimmunity Goes Local

Tertiary lymphoid structures (TLS) are frequently observed in target organs of autoimmune diseases. TLS present features of secondary lymphoid organs such as segregated T and B cell zones, presence of follicular dendritic cell networks, high endothelial venules and specialized lymphoid fibroblasts and display the mechanisms to support local adaptive immune responses toward locally displayed antigens. TLS detection in the tissue is often associated with poor prognosis of disease, auto-antibody production and malignancy development. This review focuses on the contribution of TLS toward the persistence of the inflammatory drive, the survival of autoreactive lymphocyte clones and post-translational modifications, responsible for the pathogenicity of locally formed autoantibodies, during autoimmune disease development

Fostering student agency and motivation: co-creation of a rubric for self-evaluation in an ungraded course

No one enjoys grading, neither instructors nor students. The idea is that grades provide the required incentive to learn and act as an “objective” form of evaluation. This view is especially prevalent in STEM, where practitioners pride themselves in quantitative and objective measurements. However, the science of learning tells us that grades and ranking increase competition and stress, pushing learners to engage in tasks regardless of their effectiveness. Grades have been shown to suppress interest in learning, incentivize engagement in easier tasks, and produce shallower thinking. If wanting to learn is something students and faculty can agree on, how do we get there without grading? From psychology research, we know that feedback, separated from grades, along with opportunities to reattempt work without negative consequence, are powerful drivers of the intrinsic motivation to learn. In fact, feedback loops—trying something new, getting feedback, and making changes based on feedback - are a known developmental pathway to authentic learning. In this article, I describe an experiment with a form of ungrading that involves students in the co-creation of self-assessment criteria. The goal is to create learning feedback loops, incentivize learning for learning’s sake, and give students some agency in the process of evaluation. This was conducted in an upper division Immunology course at a small liberal arts college. This paper outlines an iterative and dialogical process between students and instructional staff to craft a holistic set of criteria for the evaluation of learning. These criteria became the foundation for regular one-on-one conversations with students and a means to track progress over the semester. End-of-semester student feedback was overwhelmingly positive, citing increased motivation to learn, lower levels of anxiety, a less competitive environment, and growth as a learner. Among the few disadvantages cited were anxieties from grade ambiguity, fears about the process, and extra time, especially for the instructor. This paper highlights the ways in which this system aligns with psychosocial theories of learning, fostering an intrinsic motivation to learn utilizing principles of critical pedagogy and students as partners. It concludes with lessons learned from both the student and instructor viewpoint

Study of Split-Ring Resonators as a Metamaterial for High-Power Microwave Power Transmission and the Role of Defects

Microwave metamaterials show promise in numerous low-power applications, ranging from strip lines to antennas. In general, metamaterials allow microwave designers to obtain electromagnetic characteristics not typically available in nature, leading to new behavior as well as reductions in the size of typical devices. High-power microwave (HPM) sources were efficient in the conventional microwave source community. We consider a specific use of metamaterials as a method to reduce the size of waveguide used for power transmission, particularly, a configuration in which an array of split-ring resonators (SRRs), forming a “mu-negative” structure, allows transmission of power in a waveguide well below the cutoff frequency. This configuration would not be used in an actual HPM device, but explores the methods and considerations that might be required for developing a metamaterial structure for either making HPM sources more compact or developing new types of interaction at these high powers. For any HPM application, a microwave structure must be able to sustain high electric and magnetic fields, as well as high peak and possibly average power. The challenge for metamaterials consists of devising the subwavelength structures (a defining characteristic of metamaterials) that can sustain such fields. In particular, one must understand the sensitivity of any metamaterial system to changes in the individual elements, which in high power pertains mainly to the loss of an individual resonator element. As such a sample system, we explore the physical operating characteristics of the waveguide system loaded with an array of SRRs, particularly the role of defects on its properties. Such defects would form an important feature in any high-power application in which subwavelength structures can be damaged by high field stresses

Kuby Immunology

Even though this is nominally a seventh edition, the previous authors had written a rather weak sixth edition, and Jenni, Sharon and I wrote each chapter pretty much from scratch, changing the order of the chapters, adding in several new ones and creating what is essentially an entirely new book. Although I can already see places where we can revise and improve it for the eighth edition, I think we\u27re all still proud of what we\u27ve produced. It is worth stating that when a field changes as rapidly as ours, the production of a textbook proves to be a truly scholarly endeavor, as we read and evaluate new experiments and determine whether they indeed represent a shift in the thinking of that part of the discipline, or merely an interesting new development layered onto a pre-existing foundation. I have loved being a part of this project