Human Immune System Development and Rejection of Human Islet Allografts in Spontaneously Diabetic NOD-Rag1null IL2r null Ins2Akita Mice

Identifying critical windows in immune system development is crucial for determination of either safety or vulnerability to exposure to specific agents during rapidly changing phases of ontogeny. These phases in the human range from postconception early gestation through adolescence. A detailed understanding of these windows will facilitate avoidance of environmental toxins as well as allow improved planning for unavoidable exposures. Critical windows of immune development will be influenced by concomitant development, maturation and growth of other organ systems, thus the influence of potentially toxic exposures must be determined within a co-ordinated multisystem and multidisciplinary approach.

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Human immune system development in NOD/LtSz-scid IL2Rgnull mice after engraftment with purified cord blood derived stem cells

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0030-1269393 ◽

2011 ◽

Vol 59 (S 01) ◽

Author(s):

A Andersson ◽

S Brösel ◽

D Lange ◽

C Knosalla ◽

LD Shultz ◽

...

Keyword(s):

Stem Cells ◽

Immune System ◽

Cord Blood ◽

System Development ◽

Human Immune System ◽

Immune System Development ◽

Human Immune

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Human immune system development and survival of non-obese diabetic (NOD)-scid IL2rγnull(NSG) mice engrafted with human thymus and autologous haematopoietic stem cells

Clinical & Experimental Immunology ◽

10.1111/cei.12180 ◽

2013 ◽

Vol 174 (3) ◽

pp. 372-388 ◽

Cited By ~ 69

Author(s):

L. Covassin ◽

S. Jangalwe ◽

N. Jouvet ◽

J. Laning ◽

L. Burzenski ◽

...

Keyword(s):

Stem Cells ◽

Immune System ◽

System Development ◽

Human Immune System ◽

Haematopoietic Stem Cells ◽

Human Thymus ◽

Nsg Mice ◽

Immune System Development ◽

Human Immune

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Overview of immune system development in the dog: comparison with humans

Human & Experimental Toxicology ◽

10.1191/0960327102ht286oa ◽

2002 ◽

Vol 21 (9-10) ◽

pp. 487-492 ◽

Cited By ~ 63

Author(s):

P J Felsburg

Keyword(s):

Immune System ◽

System Development ◽

Postnatal Period ◽

Large Animal ◽

Human Immune System ◽

Potential Toxicity ◽

Clinical Model ◽

Investigational Drugs ◽

Immune System Development ◽

Human Immune

Dogs play an important role in toxicology because of their importance as a large animal, pre-clinical model for evaluating potential toxicity in human drug development including the effects of investigational drugs on the immune system. The purpose of this paper is to review the development of the canine immune system during the fetal, neonatal and postnatal periods and to compare it with that of the human immune system. Unlike rodents, the development of the canine immune system shares many similarities to that of the human. In both dogs and humans, the immune system, including the mucosal immune system, is fully developed before birth although the maturity of the immune response may continue into the postnatal period.

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Acceptive Immunity: The Role of Fucosylated Glycans in Human Host–Microbiome Interactions

International Journal of Molecular Sciences ◽

10.3390/ijms22083854 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3854

Author(s):

Svetlana Kononova ◽

Ekaterina Litvinova ◽

Timur Vakhitov ◽

Maria Skalinskaya ◽

Stanislav Sitkin

Keyword(s):

Immune System ◽

System Development ◽

Bacterial Colonization ◽

Past Century ◽

Human Immune System ◽

Immune System Development ◽

Human Immune ◽

The Relationship ◽

Symbiotic Microbiota

The growth in the number of chronic non-communicable diseases in the second half of the past century and in the first two decades of the new century is largely due to the disruption of the relationship between the human body and its symbiotic microbiota, and not pathogens. The interaction of the human immune system with symbionts is not accompanied by inflammation, but is a physiological norm. This is achieved via microbiota control by the immune system through a complex balance of pro-inflammatory and suppressive responses, and only a disturbance of this balance can trigger pathophysiological mechanisms. This review discusses the establishment of homeostatic relationships during immune system development and intestinal bacterial colonization through the interaction of milk glycans, mucins, and secretory immunoglobulins. In particular, the role of fucose and fucosylated glycans in the mechanism of interactions between host epithelial and immune cells is discussed.

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Human-like NSG mouse glycoproteins sialylation pattern changes the phenotype of human lymphocytes and sensitivity to HIV-1 infection

10.1101/404905 ◽

2018 ◽

Author(s):

Raghubendra Singh Dagur ◽

Amanda Branch Woods ◽

Saumi Mathews ◽

Poonam S. Joshi ◽

Rolen M. Quadros ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

System Development ◽

Human Immune System ◽

Hematopoietic Stem ◽

Acetylneuraminic Acid ◽

Immune System Development ◽

Human Immune ◽

Nsg Mouse ◽

Hiv 1

AbstractBackgroundThe use of immunodeficient mice transplanted with human hematopoietic stem cells is an accepted approach to study human-specific infectious diseases, like HIV-1, and to investigate multiple aspects of human immune system development. However, mouse and human are different in sialylation patterns of proteins due to evolutionary mutations of the CMP-N-acetylneuraminic acid hydroxylase (CMAH) gene that prevent formation of N-glycolylneuraminic acid from N-acetylneuraminic acid. How changes of mouse glycoproteins chemistry will affect phenotype and function of transplanted human hematopoietic stem cells and mature human immune cells in the course of HIV-1 infection is not known.ResultsWe mutated mouseCMAHon the most widely human cells transplantation strain NOD/scid-IL2Rγc-/-(NSG) mouse background using the CRISPR/Cas9 system. The new strain provides a better environment for human immune cells. Transplantation of human hematopoietic stem cells leads to broad B cells repertoire, higher sensitivity to HIV-1 infection, and enhanced proliferation of transplanted peripheral blood lymphocytes. The mice showed low effects on the clearance of human immunoglobulins and enhanced transduction efficiency of recombinant adeno-associated viral vector rAAV2/DJ8.ConclusionNSG-cmah-/-mice expand the mouse models suitable for human cells transplantation and this new model has advantages in generating a human B cell repertoire. This strain is suitable to study different aspects of the human immune system development, might provide advantages in patient-derived tissue and cell transplantation, and could allow studies of viral vectors and infectious agents that are sensitive to human-like sialylation of mouse glycoproteins.

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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

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Osteopontin Levels in Human Milk Are Related to Maternal Nutrition and Infant Health and Growth

Nutrients ◽

10.3390/nu13082670 ◽

2021 ◽

Vol 13 (8) ◽

pp. 2670

Author(s):

Aysegül Aksan ◽

Izzet Erdal ◽

Siddika Songül Yalcin ◽

Jürgen Stein ◽

Gülhan Samur

Keyword(s):

Immune System ◽

Breast Milk ◽

Infant Health ◽

Maternal Nutrition ◽

System Development ◽

Maternal Factors ◽

Immune System Development ◽

The Mean ◽

Pregnancy Weight

Background: Osteopontin (OPN) is a glycosylated phosphoprotein found in human tissues and body fluids. OPN in breast milk is thought to play a major role in growth and immune system development in early infancy. Here, we investigated maternal factors that may affect concentrations of OPN in breast milk, and the possible associated consequences for the health of neonates. Methods: General characteristics, health status, dietary patterns, and anthropometric measurements of 85 mothers and their babies were recorded antenatally and during postnatal follow-up. Results: The mean concentration of OPN in breast milk was 137.1 ± 56.8 mg/L. Maternal factors including smoking, BMI, birth route, pregnancy weight gain, and energy intake during lactation were associated with OPN levels (p < 0.05). Significant correlations were determined between body weight, length, and head circumference, respectively, and OPN levels after one (r = 0.442, p = < 0.001; r = −0.284, p = < 0.001; r = −0.392, p = < 0.001) and three months (r = 0.501, p = < 0.001; r = −0.450, p = < 0.001; r = −0.498, p = < 0.001) of lactation. A negative relation between fever-related infant hospitalizations from 0–3 months and breast milk OPN levels (r = −0.599, p < 0.001) was identified. Conclusions: OPN concentrations in breast milk differ depending on maternal factors, and these differences can affect the growth and immune system functions of infants. OPN supplementation in infant formula feed may have benefits and should be further investigated.

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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.

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