Begell House Inc.
Onco Therapeutics
OT
2694-4642
6
1-2
2015
Preface: John L. Fahey: Pioneer in New Disciplines of Human Immunology
v-vi
10.1615/ForumImmunDisTher.2015015555
Otoniel
Martinez-Maza
UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles
Christel H.
Uittenbogaart
Department of Microbiology, Immunology, and Molecular Genetics; Department of Pediatrics, David Geffen Medical School at UCLA, Los Angeles, CA 90095; University of California at Los Angeles AIDS Institute; Jonsson Comprehensive Cancer Center, David Geffen Medical School at UCLA, Los Angeles, CA 90095
Preface
Eulogy to Professor John L. Fahey: My Teacher, Collaborator, and Professional Counselor
1-2
10.1615/ForumImmunDisTher.2015015263
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
Memorial
John L. Fahey: A Man of Many Talents
3-5
10.1615/ForumImmunDisTher.2015015358
Jacob
Zighelboim
UCLA School of Medicine, Retired Professor of Medicine and Microbiology and Immunology, University of California at Los Angeles, Los Angeles, CA; Address all correspondence to: Jacob Zighelboim, MD, 614 N. Crescent Dr., Beverly Hills, CA 90210
Memorial
John L. Fahey was an accomplished scientist who contributed greatly to immunological research at the University
of California, Los Angeles (UCLA) and beyond. He was also a master mentor and teacher who cared a great deal for the welfare
of his trainees and rejoiced in their successes.
Reinvigorating Exhausted T Cells by Blockade of the PD-1 Pathway
7-17
10.1615/ForumImmunDisTher.2015014188
Junghwa
Lee
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
Eunseon
Ahn
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
Haydn T
Kissick
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
Rafi
Ahmed
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
cancer
chronic infection
immunotherapy
programmed cell death-1
T-cell exhaustion
T-cell exhaustion due to persistent antigen stimulation is a key feature of chronic viral infections and cancer. Programmed cell death-1 (PD-1) is a major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores T-cell function and improves pathogen control and tumor eradication. Immunotherapy targeting the PD-1 inhibitory receptor pathway has demonstrated significant antitumor activity. Recently, antibodies blocking PD-1 have been approved for use in cancer patients. In this review, we summarize the role of the PD-1 pathway in chronic infection and cancer and the therapeutic potential of PD-1-directed immunotherapy in patients with chronic infection or cancer.
Measurement of Circulating Cytokines and Immune-Activation Markers by Multiplex Technology in the Clinical Setting: What Are We Really Measuring?
19-22
10.1615/ForumImmunDisTher.2015014162
Najib
Aziz
Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles, Los Angeles, CA 90095-1772
cytokine
immunology
multiplex assay
Measurement of circulating cytokine levels can provide important information in the study of the pathogenesis of disease. John L. Fahey was a pioneer in the measurement of circulating cytokines and immune-activation markers and a leader in the quality assessment/control of assays for measurement of circulating cytokines. Insights into the measurement of circulating cytokines, including consideration of multiplex assays, are presented here.
Lessons of Life and Science from Dr. John L. Fahey
23-24
10.1615/ForumImmunDisTher.2015014268
Susan
Plaeger
1819 Quincy Street N.W., Washington, D.C. 20011
postdoctoral fellows
creativity
John L. Fahey guided more than 70 postdoctoral fellows during his long science career. Although a tough taskmaster, John taught his fellows lessons critical to good science, in particular, the need for creativity, which he expressed in abundance
Memories of John L. Fahey, M.D.'s Clinical Immunology Society Years
25-26
10.1615/ForumImmunDisTher.2015014920
Susan
Kanowith-Klein
UCLA
Clinical Immunology Society
John Fahey
John L. Fahey, M.D. headed a team of researchers, clinicians, and other academic staff throughout his career at the University of California, Los Angeles, working with them in various capacities. Here, I recount my memories of working with Dr. Fahey during the early years of the Clinical Immunology Society
Worms and Humans: A Happy Divorce?
27-32
10.1615/ForumImmunDisTher.2015015300
Hannah
Akuffo
Department of Medicine, Karolinska Institutet, Stockholm, Sweden
Sven
Britton
Department of Medicine, Karolinska Institutet, Stockholm, Sweden
Thomas
Schön
Department of Medicine, Karolinska Institutet, Stockholm, Sweden
autoimmunity
confection
deworming
helminths/worms
tuberculosis
Chronic asymptomatic worm infection, often in combination with tuberculosis (TB), is common in low-income countries. Indeed, a life without worm infestation, as is now the case in most high-income countries, is a recent condition for humankind. Worms and Mycobacterium tuberculosis give rise to different immune response patterns (Th2 vs. Th1 driven), and we have studied whether chronic worm infection affects the susceptibility to and control of TB in the low income country of Ethiopia. Our results, as well of those in the general literature, are inconclusive, although we have some rather strong data in support of adult deworming in relation to vaccination with bacillus Calmette-Guerin (BCG) against TB. In addition, we discuss briefly the putative relationship between chronic worm infestation and autoimmunity/allergy.
Human T-Cell Development and Thymic Egress: An Infectious Disease Perspective
33-49
10.1615/ForumImmunDisTher.2015014226
Rachel S.
Resop
Department of Microbiology, Immunology, and Molecular Genetics; Department of Pediatrics, David Geffen Medical School at UCLA, Los Angeles, CA 90095
Christel H.
Uittenbogaart
Department of Microbiology, Immunology, and Molecular Genetics; Department of Pediatrics, David Geffen Medical School at UCLA, Los Angeles, CA 90095; University of California at Los Angeles AIDS Institute; Jonsson Comprehensive Cancer Center, David Geffen Medical School at UCLA, Los Angeles, CA 90095
human immunodeficiency virus
human immunology
humanized mice
migration
murine models
S1P-R1
S1P- R2
sphingosine-1-phosphate
T-cell reconstitution
thymic egress
thymocyte development
thymus
Emigration of mature naive CD4 SP T cells from the human thymus to the periphery is not fully understood, although elucidation of the mechanisms that govern egress of T cells is crucial to understanding both basic immunology and the immune response in diseases such as HIV infection. Recent work has brought to light the requirement for sphingosine-1-phosphate (S1P) and its receptors in a variety of fields including mature naive T-cell egress from the thymus of mice. We are examining the expression and function of this novel requisite T-cell egress receptor within the human thymus, characterizing changes observed in the expression and function of this receptor in infectious diseases. To perform this work, we use a variety of humanized murine models reviewed in this article. Future work in the field of T-cell egress, especially as it pertains to S1P receptors, should advance the fields of basic T-cell immunology and immunopathology and open new avenues for exploration into novel therapeutics.
Fond Memories of John Fahey
51-52
10.1615/ForumImmunDisTher.2016015391
Roger
Detels
UCLA Fielding School of Public Health, Department of Epidemiology, Center for the Health Sciences, Room 71-267,
P. O. Box 951772, Los Angeles, CA 90095-1772
AIDS
immunology
Multicenter AIDS Cohort Study
John Fahey was one of the first investigators to study the then-new acquired immune deficiency syndrome (AIDS).
He made major contributions to the design of the Multicenter AIDS Cohort Study (MACS), and vigorously promoted novel and
high-quality science as the MACS evolved. His contributions are highly valued.
Memories of John Fahey and His Contributions to the Multicenter AIDS Cohort Study (MACS)
53-55
10.1615/ForumImmunDisTher.v6.i1-2.110
John Phillip
Phair
Feinberg School of Medicine, Northwestern University, Chicago, IL
Roger
Detels
UCLA Fielding School of Public Health, Department of Epidemiology, Center for the Health Sciences, Room 71-267,
P. O. Box 951772, Los Angeles, CA 90095-1772
Joseph
Margolick
Bloomberg School of Public Health, John Hopkins University, Baltimore, MD
Charles R.
Rinaldo
Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA; Infectious Diseases and Microbiology, Pathology, University of Pittsburgh, Pittsburgh, PA
Lisa
Jacobson
Bloomberg School of Public Health, John Hopkins University, Baltimore, MD
Otoniel
Martinez-Maza
UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles
Steven
Wolinsky
Feinberg School of Medicine, Northwestern University, Chicago, IL
Alvaro
Muñoz
Bloomberg School of Public Health, John Hopkins University, Baltimore, MD
AIDS
immunology
natural history
John Fahey was an integral member of the small group of investigators who developed the Multicenter AIDS Cohort Study (MACS) in the early 1980s. A major research theme in the MACS was defining immune system changes in men at risk for developing AIDS. John's experience and expertise provided a solid grounding for the immunologic investigations conducted in the MACS. Additionally, he contributed enormously to the science of the MACS and pioneered the critical evaluation of serologic methods of documenting infection with HIV and T cell phenotyping. Perhaps most importantly, John recruited key new investigators to the MACS, and worked closely with the original MACS investigators to create a structure that promoted scientific innovation, openness, and the ability to quickly respond to emerging research themes.
A Brief Chronicle of CD4 as a Biomarker for HIV/AIDS: A Tribute to the Memory of John L. Fahey
57-65
10.1615/ForumImmunDisTher.2016014169
Jonathan M.
Kagan
Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States Department of Health and Human Services, Rockville, MD
Ana M.
Sanchez
Duke Human Vaccine Institute and Center for HIV/AIDS, Duke University, Durham, NC
Alan
Landay
Rush University Medical Center, Chicago, IL
Thomas N.
Denny
Duke Human Vaccine Institute and Center for HIV/AIDS, Duke University, Durham, NC
biomarkers
CD4
HIV/AIDS
immune monitoring
flow cytometry w
Foundational cellular immunology research of the 1960s and 1970s, together with the advent of monoclonal antibodies and flow cytometry, provided the knowledge base and the technological capability that enabled the elucidation of the role of CD4 T cells in HIV infection. Research identifying the sources and magnitude of variation in CD4 measurements, standardized reagents and protocols, and the development of clinical flow cytometers all contributed to the feasibility of widespread CD4 testing. Cohort studies and clinical trials provided the context for establishing the utility of CD4 for prognosis in HIV-infected persons, initial assessment of in vivo antiretroviral drug activity, and as a surrogate marker for clinical outcome in antiretroviral therapeutic trials. Even with sensitive HIV viral load measurement, CD4 cell counting is still utilized in determining antiretroviral therapy eligibility and time to initiate therapy. New point of care technologies are helping both to lower the cost of CD4 testing and enable its use in HIV test and treat programs around the world.
Programming T cell Killers for an HIV Cure: Teach the New Dogs New Tricks and Let the Sleeping Dogs Lie
67-77
10.1615/ForumImmunDisTher.2016014160
Kellie N.
Smith
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA; Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA
Robbie B.
Mailliard
Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA
Charles R.
Rinaldo
Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA; Infectious Diseases and Microbiology, Pathology, University of Pittsburgh, Pittsburgh, PA
CTL
dendritic cells
HIV-1
immunotherapy
Despite the success of combination antiretroviral therapy (cART), a latent viral reservoir persists in HIV-1-infected persons. Unfortunately, endogenous cytotoxic T lymphocytes (CTLs) are unable to control viral rebound when patients are removed from cART. A "kick and kill" strategy has been proposed to eradicate this reservoir, whereby infected T cells are induced to express viral proteins via latency-inducing drugs followed by their elimination by CTLs. It has yet to be determined if stimulation of existing HIV-1-specific CTL will be sufficient, or if new CTLs should be primed from naive T cells. In this review, we propose that dendritic cells (DCs), the most potent antigen presenting cells, act as dog trainers and can induce T cells (the dogs) to do magnificent tricks. We propose the hypothesis that an HIV-1 cure will require targeting of naive T cells and will necessitate "teaching new dogs new tricks" while avoiding activation of potentially dysfunctional endogenous memory CTLs (letting the sleeping dogs lie).
Immune Activation: Contribution to AIDS-Associated Non-Hodgkin Lymphoma
79-90
10.1615/ForumImmunDisTher.2016014177
Marta
Epeldegui
Department of Obstetrics & Gynecology, David Geffen School of Medicine at UCLA, and UCLA AIDS Institute, Los Angeles, CA; University of California at Los Angeles, Los Angeles, CA 90095
Otoniel
Martinez-Maza
UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles
AIDS
HIV
immune activation
lymphoma
NHL
HIV infection is associated with a greatly elevated risk for the development of non-Hodgkin lymphoma (NHL), which while diminished, remains elevated in the highly active antiretroviral therapy (HAART) era. Chronic B cell activation, driven by contact with HIV virions, B cell-stimulatory cytokines, viruses (EBV, HPV, HCV), and by high levels of antigenic stimulation occurs in HIV infected persons, and it is seen at even higher levels in those who go on to develop AIDS-NHL. Evidence from multiple studies indicates that elevated serum levels of several B cell-stimulatory cytokines and biomarkers are seen preceding AIDS-NHL, as well as in immunocompetent persons that develop NHL. Phenotypic changes in circulating B cells also are seen preceding AIDS-NHL, including the expression of AICDA, and of cell-surface molecules and miRNA that are associated with activated B cells. HAART only partially normalizes the immune system of treated HIV+ persons as they still show clear evidence for ongoing inflammation and immune activation in, even those who show complete suppression of HIV viremia. Together, this provides ample evidence to support the notion that chronic activation of B cells contributes to the genesis of B cell lymphomas.
Experimental Approaches for Eliminating Latent HIV
91-99
10.1615/ForumImmunDisTher.2016015242
Matthew D.
Marsden
Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, CA
Jerome A.
Zack
Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, CA; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA
activation
latency
reservoir
Antiretroviral therapy (ART) can reduce HIV viral loads to undetectable levels and prevent disease progression. However, HIV persists in rare cellular reservoirs within ART-treated patients and rapidly reemerges if ART is stopped. Latently infected CD4+ T cells represent a major reservoir of HIV that persists during ART. Therefore, a cure for HIV must include methods that either permanently inactivate or eliminate latent virus. Experimental methods under investigation for eliminating latently infected cells include transplantation/gene therapy approaches intended to deplete the infected cells and replace them with HIV-resistant ones, and DNA editing strategies that are capable of damaging or excising non-expressing HIV proviruses. Alternatively, "activation-elimination", also known as "shock and kill", approaches aim to induce expression of latent virus, allowing the virus to be eliminated by viral cytopathic effects, immune effector mechanisms, or additional cells/antibodies that specifically target and kill cells expressing HIV proteins. Here, we describe these experimental approaches for eliminating latent HIV along with other recent advances in HIV cure research.
Development of Indian HIV-1 Subtype C Vaccine Candidates
101-107
10.1615/ForumImmunDisTher.2016014508
Pradeep
Seth
Seth Research Foundation, Gurgaon, Haryana, India
Swati Seth
Yadav
School of Nursing, University of California, Los Angeles, CA
DNA vaccine
HIV-1
HIV-1 subtype C
HIV vaccine
preclinical immunogenicity
prime-boost regimen
rDNA
rMVA
With 2.1 million HIV infected persons, India has the third highest number of people living with HIV in the world. Although antiretroviral therapy has contained the epidemic to a great extent, the possibility of containing virus replication in infected individuals is getting slimmer with the emergence of HIV resistance to these drug regimens. Development of a vaccine against human immunodeficiency virus type-1 (HIV-1) is the mainstay for controlling the AIDS pandemic. Since in India more than 90% of HIV infections are due to HIV-1 subtype C, it is imperative that a vaccine from locally circulating Indian HIV-1 subtype C be developed that would induce a robust immune response in recipients. This paper is a review of the work done on the development of candidate recombinant DNA-MVA vaccine formulations expressing the human immunodeficiency virus-1 env-gp120, gagprotease, tat, and nef genes from HIV-1 Indian subtype C. These constructs induced robust humoral as well as cell mediated immune responses in experimental animals, including nonhuman primates, in terms of magnitude and breadth. These constructs are slated for human trials under the aegis of the Indian Council of Medical Research.
The Legacy of John L. Fahey in Psychoneuroimmunology Research
109-118
10.1615/ForumImmunDisTher.2016015366
Elizabeth Crabb
Breen
UCLA Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior; Department of Psychiatry & Biobehavioral Sciences and AIDS Institute, David Geffen School of Medicine at UCLA, University of California, 300 Medical Plaza, Room 3160A, Los Angeles, CA 90095-7076
immune system
intervention
mind-body interactions
psychoneuroimmunology
John Fahey collaborated with Norman Cousins and many other colleagues at the University of California, Los Angeles, who were key to the establishment and development of the field of psychoneuroimmunology (PNI) research. PNI, which explores the interactions between the immune system, the mind (thoughts, responses, and behaviors), and the brain (via the central nervous system), has as its ultimate goal the improvement of human health through the better understanding of these interactions. In this commentary, John Fahey's early contributions to PNI research, especially in the areas of cell-mediated immunity, immune system activation, and inflammation, will be reviewed, followed by descriptions of some more recent work by others associated with the UCLA Cousins Center for PNI that illustrate John's ongoing legacy in this expanding field.
Translational Psychoneuroimmunology in Oral Biology and Medicine
119-131
10.1615/ForumImmunDisTher.2016014150
Francesco
Chiappelli
UCLA School of Dentistry (Oral Biology & Medicine), Los Angeles, CA; Evidence-Based Decision Practice-Based Research Network, Los Angeles, CA
Andre
Barkhordarian
UCLA School of Dentistry (Oral Biology & Medicine), Los Angeles, CA; Evidence-Based Decision Practice-Based Research Network, Los Angeles, CA
Quyen
Bach
UCLA School of Dentistry (Oral Biology & Medicine), Los Angeles, CA
Gary
Demerjian
UCLA School of Dentistry (Oral Biology & Medicine), Los Angeles, CA; Evidence-Based Decision Practice-Based Research Network, Los Angeles, CA; Center for TMJ and Sleep Therapy, Los Angeles, CA
blood-brain barrier
evidence-based health care
neuroinflammation
psychoneuroimmunology
temporomandibular joint disorders
TH17/TH9
translational science
Tregs
As we celebrate our teacher, our mentor, our friend, Professor John L. Fahey (1924−2014), emeritus professor in the Departments of Microbiology, Immunology and Molecular Genetics and of Medicine at UCLA (1971−2014), it is clear that we all have a personal story that intersects and intertwines with the greater history of the contribution to science and to our own individual growth as scientists proffered by this brilliant academician. To be clear, Dr. Fahey was a man of superlative firm kindness, of unwavering dedication to the growth and fulfillment of his students and trainees, and of deep and patient respect for each of our deep-seated interests. His body of work is also, undoubtedly, an immeasurable contribution to the fundamental science of basic and clinical immunology. Professor Fahey was many years ahead of everyone in his field, and in allied fields of his interest such as psychoneuroimmunology. Indeed, he was one of the four founding members of the Cousins Center for Psychoneuroimmunology at UCLA in the mid- to late 1980s. It is in the latter context, perhaps, that he excelled in the flexibility of his creative mind by helping foster, at UCLA, an environment where the study of the immune system could be carried out beyond the limits of traditional scientific areas. Accordingly, he molded the minds of many of his students and mentees. To be sure, I was most fortunate to be among them during my three years' dual postdoctoral fellowships in his research group (UCLA Program in Psychoneuroimmunology, 1987−1990; NIH: Fundamental and Clinical Immunology, 1988−1990).