On the use of Gillespie stochastic simulation algorithm in a model of the human immune system response to the Yellow Fever vaccine

A cardiovascular stent is a cylindrical wire mesh structure that is permanently introduced into an artery during angioplasty (balloon dilatation) to act as a scaffold, thus preventing elastic recoil and/or sudden collapse of the damaged artery. While cardiovascular stents virtually eliminate elastic recoil and/or collapse of the artery, recognition of the stent as a foreign material triggers a human immune system response causing re-closure, or restenosis, of the artery. A recent advancement to counteract restenosis is to employ drug-eluting stents to locally deliver immunosuppressant and antiproliferative drugs.

Download Full-text

Humanized Mice for Live-Attenuated Vaccine Research: From Unmet Potential to New Promises

Vaccines ◽

10.3390/vaccines8010036 ◽

2020 ◽

Vol 8 (1) ◽

pp. 36 ◽

Cited By ~ 1

Author(s):

Aoife K. O’Connell ◽

Florian Douam

Keyword(s):

Immune System ◽

Immune Responses ◽

Rational Design ◽

Cost Effective ◽

Yellow Fever Vaccine ◽

Human Immune System ◽

Live Attenuated Vaccine ◽

The Past ◽

Immunological Mechanisms ◽

Human Immune

Live-attenuated vaccines (LAV) represent one of the most important medical innovations in human history. In the past three centuries, LAV have saved hundreds of millions of lives, and will continue to do so for many decades to come. Interestingly, the most successful LAVs, such as the smallpox vaccine, the measles vaccine, and the yellow fever vaccine, have been isolated and/or developed in a purely empirical manner without any understanding of the immunological mechanisms they trigger. Today, the mechanisms governing potent LAV immunogenicity and long-term induced protective immunity continue to be elusive, and therefore hamper the rational design of innovative vaccine strategies. A serious roadblock to understanding LAV-induced immunity has been the lack of suitable and cost-effective animal models that can accurately mimic human immune responses. In the last two decades, human-immune system mice (HIS mice), i.e., mice engrafted with components of the human immune system, have been instrumental in investigating the life-cycle and immune responses to multiple human-tropic pathogens. However, their use in LAV research has remained limited. Here, we discuss the strong potential of LAVs as tools to enhance our understanding of human immunity and review the past, current and future contributions of HIS mice to this endeavor.

Download Full-text

Faculty Opinions recommendation of The genetic architecture of the human immune system: a bioresource for autoimmunity and disease pathogenesis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725390605.793505391 ◽

2015 ◽

Author(s):

Toshihiro Nakajima ◽

Satoko Aratani

Keyword(s):

Immune System ◽

Genetic Architecture ◽

Human Immune System ◽

Disease Pathogenesis ◽

System A ◽

Human Immune

Download Full-text

NCMP-05. DECODING THE IMMUNE SYSTEM RESPONSE TO LEPTOMENINGEAL METASTASIS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.517 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii124-ii124

Author(s):

Jan Remsik ◽

Xinran Tong ◽

Ugur Sener ◽

Danille Isakov ◽

Yudan Chi ◽

...

Keyword(s):

Immune System ◽

Immune Cells ◽

Leptomeningeal Metastasis ◽

System Response ◽

Idle State ◽

The Central Nervous System ◽

Health And Disease ◽

Immune System Response ◽

Therapeutic Protocols ◽

Brain And Spinal Cord

Abstract For decades, the central nervous system was considered to be an immune privileged organ with limited access to systemic immunity. However, the leptomeninges, the cerebrospinal fluid (CSF)-filled anatomical structure that protects the brain and spinal cord, represent a relatively immune-rich environment. Despite the presence of immune cells, complications in the CSF, such as infectious meningitis and a neurological development of cancer known as leptomeningeal metastasis, are difficult to treat and are frequently fatal. We show that immune cells entering the CSF are held in an ‘idle’ state that limits their cytotoxic arsenal and antigen presentation machinery. To understand this underappreciated neuroanatomic niche, we used unique mouse models and rare patient samples to characterize its cellular composition and critical signaling events in health and disease at a single-cell resolution. Revealing the mediators of CSF immune response will allow us to re-evaluate current therapeutic protocols and employ rational combinations with immunotherapies, therefore turning the patient’s own immune system into an active weapon against pathogens and cancer.

Download Full-text

721 AT1412, a patient-derived CD9 antibody in preclinical development promoting tumor immune infiltration and inducing tumor rejection

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0721 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A763-A763

Author(s):

Remko Schotte ◽

Julien Villaudy ◽

Martijn Kedde ◽

Wouter Pos ◽

Daniel Go ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

Tumor Cells ◽

Tumor Rejection ◽

Human Immune System ◽

Preclinical Development ◽

High Affinity ◽

Human Immune ◽

A375 Melanoma

BackgroundAdaptive immunity to cancer cells forms a crucial part of cancer immunotherapy. Recently, the importance of tumor B-cell signatures were shown to correlate with melanoma survival. We investigated whether tumor-targeting antibodies could be isolated from a patient that cured (now 13 years tumor-free) metastatic melanoma following adoptive transfer of ex vivo expanded autologous T cells.MethodsPatient‘s peripheral blood B cells were isolated and tested for the presence of tumor-reactive B cells using AIMM’s immmortalisation technology. Antibody AT1412 was identified by virtue of its differential binding to melanoma cells as compared to healthy melanocytes. AT1412 binds the tetraspanin CD9, a broadly expressed protein involved in multiple cellular activities in cancer and induces ADCC and ADCP by effector cells.ResultsSpontaneous immune rejection of tumors was observed in human immune system (HIS) mouse models implanted with CD9 genetically-disrupted A375 melanoma (A375-CD9KO) tumor cells, while A375wt cells were not cleared. Most notably, no tumor rejection of A375-CD9KO tumors was observed in NSG mice, indicating that blockade of CD9 makes tumor cells susceptible to immune rejection.CD9 has been described to regulate integrin signaling, e.g. LFA-1, VLA-4, VCAM-1 and ICAM-1. AT1412 was shown to modulate CD9 function by enhancing adhesion and transmigration of T cells to endothelial (HUVEC) cells. AT1412 was most potently enhancing transendothelial T-cell migration, in contrast to a high affinity version of AT1412 or other high affinity anti-CD9 reference antibodies (e.g. ALB6). Enhanced immune cell infiltration is also observed in immunodeficient mice harbouring a human immune system (HIS). AT1412 strongly enhanced CD8 T-cell and macrophage infiltration resulting in tumor rejection (A375 melanoma). PD-1 checkpoint blockade is further sustaining this effect. In a second melanoma model carrying a PD-1 resistant and highly aggressive tumor (SK-MEL5) AT1412 together with nivolumab was inducing full tumor rejection, while either one of the antibodies alone did not.ConclusionsThe safety of AT1412 has been assessed in preclinical development and is well tolerated up to 10 mg/kg (highest dose tested) by non human primates. AT1412 demonstrated a half-life of 8.5 days, supporting 2–3 weekly administration in humans. Besides transient thrombocytopenia no other pathological deviations were observed. No effect on coagulation parameters, bruising or bleeding were observed macro- or microscopically. The thrombocytopenia is reversible, and its recovery accelerated in those animals developing anti-drug antibodies. First in Human clinical study is planned to start early 2021.Ethics ApprovalStudy protocols were approved by the Medical Ethical Committee of the Leiden University Medical Center (Leiden, Netherlands).ConsentBlood was obtained after written informed consent by the patient.

Download Full-text