scholarly journals Efficient Acquisition of Fully Human Antibody Genes against Self-Proteins by Sorting Single B Cells Stimulated with Vaccines Based on Nitrated T Helper Cell Epitopes

2019 ◽  
Vol 2019 ◽  
pp. 1-16
Author(s):  
Liangliang Jiang ◽  
Tao Jiang ◽  
Jianhua Luo ◽  
Yanliang Kang ◽  
Yue Tong ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
B Cells ◽  
B Cell ◽  
Immune Tolerance ◽  
Human Antibody ◽  
T Helper ◽  
Human Immune System ◽  
Helper Epitope ◽  
Human Immune

Single B cell antibody technology is a method for isolating antigen-specific B cells from human peripheral blood and obtaining antibody genes in developing antibody drugs. However, owing to immune tolerance to autoantigen, human autoantigen-specific B cells are difficult to acquire by conventional single B cell technology. In this study, we constructed a nitrated T-cell epitope named NitraTh by incorporating p-nitrophenylalanine into a universal T helper epitope. NitraTh had enhanced ability to activate CD4+ T cells and can be recognized by CD4+ T cells with different HLA class II haplotypes. This NitraTh can also break immune tolerance to autoantigens, such as human epidermal growth factor receptor 2 (HER2) and cannabinoid receptor 1, and induce strong specific IgM+ B cell responses in vitro. HER2-NitraTh vaccine can also stimulate the generation of HER2-specific IgG+ B cells in human immune system mice, which was established by cotransplanting lymphocytes and autologous dendritic cells in immunodeficient mice. We obtained 30 fully human IgG antibody genes by sorting single B cells from the human immune system mice immunized with HER2-NitraTh vaccine. The analysis of antibody genes showed that sorted B cells underwent the extensive somatic mutation of the antibody genes. We randomly selected eight genes for cloning, six of which expressed antibodies that can bind to HER2. Hence, we provided a convenient and effective method in acquiring fully human antibody genes against self-proteins, which can be used in developing therapeutic antibody drugs.

scholarly journals Central human B cell tolerance manifests with a distinctive cell phenotype and is enforced via CXCR4 signaling in hu-mice

2021 ◽  
Vol 118 (16) ◽  
pp. e2021570118
Author(s):  
Thiago Alves da Costa ◽  
Jacob N. Peterson ◽  
Julie Lang ◽  
Jeremy Shulman ◽  
Xiayuan Liang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune System ◽  
B Cells ◽  
B Cell ◽  
Cell Tolerance ◽  
Human Immune System ◽  
B Cell Tolerance ◽  
Autoreactive B Cells ◽  
Cell Clones ◽  
Human Immune

Central B cell tolerance, the process restricting the development of many newly generated autoreactive B cells, has been intensely investigated in mouse cells while studies in humans have been hampered by the inability to phenotypically distinguish autoreactive and nonautoreactive immature B cell clones and the difficulty in accessing fresh human bone marrow samples. Using a human immune system mouse model in which all human Igκ+ B cells undergo central tolerance, we discovered that human autoreactive immature B cells exhibit a distinctive phenotype that includes lower activation of ERK and differential expression of CD69, CD81, CXCR4, and other glycoproteins. Human B cells exhibiting these characteristics were observed in fresh human bone marrow tissue biopsy specimens, although differences in marker expression were smaller than in the humanized mouse model. Furthermore, the expression of these markers was slightly altered in autoreactive B cells of humanized mice engrafted with some human immune systems genetically predisposed to autoimmunity. Finally, by treating mice and human immune system mice with a pharmacologic antagonist, we show that signaling by CXCR4 is necessary to prevent both human and mouse autoreactive B cell clones from egressing the bone marrow, indicating that CXCR4 functionally contributes to central B cell tolerance.

scholarly journals Diffuse Large B Cell Pdtx in Humanized Mice Are Valuable Models to Study Host-Lymphoma Interactions and Immune-Modulating Agents

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2406-2406
Author(s):  
Giorgia Zanetti ◽  
Giuseppina Astone ◽  
Luca Cappelli ◽  
William Chiu ◽  
Maria Teresa Cacciapuoti ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Ex Vivo ◽  
Human Immune System ◽  
Human T Cells ◽  
Human Immune

Abstract Introduction: Immunotherapy is a promising therapeutic intervention for cancer treatment. Activation of the immune system via checkpoint blockade has been shown to produce antitumor responses in patients with both solid and hematological tumors. However, many patients do not respond to checkpoint inhibitors, and additional therapies are needed to treat these patients. Testing immunotherapies requires a functional human immune system; thus, it is difficult to evaluate their effectiveness using conventional experimental models. For this reason, establishing in vivo models that closely reproduce not only human tumors, but also their interactions with the human immune system, has become mandatory. Methods: We developed a humanized mouse model and combined it with a patient-derived tumor xenograft (PDTX). Humanized mice (HuMice) were generated by transplantation of cord blood or mobilized peripheral blood CD34+ hematopoietic stem and progenitor cells into preconditioned immunodeficient mice. We compared human engraftment in 3 different mouse strains: NSG (NOD.Cg-Prkdc scidIl2rg tm1Wjl/SzJ), NSGS (NOD.Cg-Prkdc scidIl2rg tm1Wjl Tg(CMV-IL3,CSF2,KITLG)1Eav/MloySzJ) and NBSGW (NOD.Cg-Kit W-41J Tyr + Prkdc scid Il2rg tm1Wjl/ThomJ). Immune cell profiling and distribution was performed using flow cytometry and immunohistochemistry. The B cell receptor (BCR) repertoire was evaluated using an RNA-based NGS assay. To evaluate the maturation and functionality of T cells developing in HuMice we performed proliferation, degranulation and intracellular cytokine staining. Results: Two months after CD34+ cell transplantation, we observed high levels of human hematopoietic chimerism in all the 3 strains. NSGS mice supported high-level chimerism as early as 1 month after transplantation, with more than 25% of human CD45+ cells in the blood. In all mice the majority of human circulating leukocytes were CD19+ B cells. An early appearance of CD3+ human T cells was detected in NSGS mice as compared to the other strains. Notably, the T cell expansion correlated with a decrease in relative B cell abundance while the myeloid cell contribution to the graft remained steady. We documented the differentiation of CD4+ and CD8+ human T cells at a 2:1 ratio. The characterization of the T cell subsets revealed that the majority was represented by CD45RA-CCR7- effector memory cells in both the spleen and the blood of HuMice. Nevertheless, recipient mice did not exhibit overt signs of graft-versus-host disease. We also evaluated the cytotoxic potential of T cells isolated from the spleen of HuMice: ex vivo peptide antigen (i.e. EBV) presentation let to generation of effective and specific cytotoxic T-cells. After assessing a functional human immune system reconstitution in HuMice, we challenged them in vivo with low-passage tumor fragments from a diffuse large B cell lymphoma (DLBCL) PDTX. All tumor implants were successfully engrafted in both HuMice and non-humanized controls. Remarkably, all the 3 HuMice strains showed a significant reduction in the tumor volume and/or eradication compared to matched non-humanized controls. Flow cytometry analysis of the peripheral blood of humanized PDTX revealed that the tumor engraftment elicited a significant expansion of CD3+ T cells and cytotoxic CD8+ lymphocytes. Moreover, tumors developing in HuMice exhibited intermediate to high levels of tumor infiltrating T lymphocytes commingling with the neoplastic B cells, as determined by immunohistochemistry. Large areas of necrosis were often observed in PDTX of HuMice. Infiltrating CD3+ cells were TIGIT, PD-1 and Lag-3 positive, and did not efficiently proliferate ex vivo: all features consistent with an exhaustion phenotype. PDTX of HuMice often displayed larger areas of necrosis. Conclusions: Collectively, our data demonstrate that a robust reconstitution can be achieved in different strains of immunocompromised mice and that HuMice elicit effective anti-lymphoma responses. PDTX HuMice represent a powerful platform to study host-tumor interactions, and to test novel immune-based strategies (CAR-T, bifunctional Abs) and new pharmacological approaches to counteract T-cell exhaustion. Figure 1 Figure 1. Disclosures Scandura: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Research Funding; MPN-RF (Foundation): Research Funding; CR&T (Foudation): Research Funding; European Leukemia net: Honoraria, Other: travel fees . Roth: Janssen: Consultancy; Merck: Consultancy.

Neonatal NOD/SCID/IL2rg-Null Mice Support the Functional Development of Human Hematopoietic and Immune Systems.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2781-2781 ◽  
Author(s):  
Fumihiko Ishikawa ◽  
Masaki Yasukawa ◽  
Bonnie Lyons ◽  
Shuro Yoshida ◽  
Leonard D. Shultz ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
B Cells ◽  
Peripheral Blood ◽  
Human Immune System ◽  
Immune Systems ◽  
New Model ◽  
Cd34 Cells ◽  
Human Immune

Abstract (Purpose) We aimed to develop a new model for studying the development of a human hematopoietic and immune systems in vivo. (Methods) In order to establish a new model of xenogeneic transplantation, we establish an immune-compromised strain, NOD.Cg-PrkdcscidIL2rgtmlWjl/Sz (NOD/SCID/IL2rg-null) mice by backcrossing a complete null mutation of the IL2 receptor common gamma chain (IL2rg) onto the NOD/SCID background. 1 x 105 human CB-derived lineage antigen negative (Lin−) CD34+ cells were intravenously transplanted into newborn NOD/SCID/IL2rg-null mice following 100cGy irradiation. At 3 months post-transplantation, the engraftment of human cells was evaluated by flow cytometric analysis, immunostaining, and functional assays for production of human immunoglobulin and T-cell cytotoxicity against allogeneic cells. (Results) NOD/SCID/IL2rg-null mice showed extremely low activity of NK cells along with the complete lack of mature B cells and T cells. During post-natal development of the NOD/SCID/IL2rg-null mice, a human hematopoietic system was developed following injection of human CB-derived Lin-CD34+ cells. In BM of the recipient mice, human glycophorin A+ erythroid cells were present at 9.5 +/− 6.2% (n=5), and human CD41+ megakaryocytes were present at 1.64 +/− 0.42% (n=5). Human CB-derived Lin−CD34+ cells generated multi-lineage leukocytes, CD33+ myeloid cells, CD19+ B cells, and CD3+ T cells. The engraftment level of human CD45+ cells in peripheral blood was significantly higher (68.9 +/− 11.6%, n=5) in NOD/SCID/IL2rg-null mice than that in NOD/SCID/b2mnull mice (12.4 +/− 5.9%, n=4). Mature erythrocytes and platelets were identified in peripheral blood. The xenogeneic environment supported the systemic development of a human immune system, containing each stage of B cells and T cells in primary and secondary lymphoid tissues. CD34+CD19+ pro-B cells, CD10+CD19+ B cells, and CD19+CD20hi mature B cells were identified in the BM and spleen. Immature CD4+CD8+ double positive T cells were the major cell populations in the thymus, while spleen contained abundant single positive T cells at 1.39 +/− 0.61 (n=5) CD4/CD8 ratio, suggesting that human CB stem/progenitor-derived T cells underwent the maturation and proliferation similarly as identified in human body. Transplanted human stem cells reconstituted mucosal immunity in intestinal tracts as evidenced by human IgA+ B cells and CD3+ T cells. Adaptive human immune system cooperatively functioned in xenogeneic environment to produce antigen-specific human IgM and IgG antibodies, when engrafted mice were immunized with ovalbumin. Furthermore, human CD4+ T cells as well as CD8+ T cells generated in the xenogeneic host exerted cytotoxicity against allogeneic target cells. (Conclusion) The neonatal NOD/SCID/IL2rg-null model will facilitate studying post-natal development of the human hematopoietic and immune systems and for studying of human immune surveillance in vivo against exogenous antigens.

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

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.

Multidimensional Flow Cytometric (MFC) Analysis of the Immune System of Multiple Myeloma (MM) Patients Achieving Long Term Disease Control

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 810-810
Author(s):  
Roberto J. Pessoa Magalhaes ◽  
María-Belén Vidriales ◽  
Bruno Paiva ◽  
Maria-Victoria Mateos ◽  
Norma C. Gutierrez ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
B Cells ◽  
Disease Control ◽  
B Cell ◽  
Nk Cells ◽  
Cell Populations ◽  
High Dose ◽  
Newly Diagnosed

Abstract Abstract 810FN2 Increasing evidence shows that a small fraction of MM patients (pts) treated with high-dose therapy followed by autologous stem cell transplantation achieve long-term remission. Interestingly, this is not restricted to pts in complete response (CR), since those that revert to a monoclonal gammopathy of undetermined significance (MGUS) profile may also achieve long-term remission, despite the persistence of residual myeloma plasma cells (PCs). These results suggest that in addition to the anti-myeloma therapy, other factors may play a role in the control of the disease. Herein, we used 8-color MFC for detailed characterization of the structural components of the immune system and hematopoietic precursor cells (HPC) in paired bone marrow (BM) and peripheral blood (PB) samples from 26 MM patients in long-term disease control (LTDC): 9 in continuous CR and 17 who reverted to an MGUS profile and that subsequently showed stable disease without treatment for ≥5 years (median of 9 years; range, 5–19). As controls, paired BM and PB samples from 23 newly-diagnosed MGUS and 16 MM pts, together with 10 healthy adults (HA), were studied in parallel. In all BM and PB samples the distribution of the major T- (CD4, CD8, Tregs and γδ), NK- (CD56dim and CD56bright) and B-cell subsets (Pro-B, Pre-B, naïve and memory), in addition to normal PCs, dendritic cell (DC) subsets (plasmacytoid, myeloid and monocytic), monocytes, and CD34+ HPC (myeloid and lymphoid), were studied. The percentage and absolute count of each cell population was analysed in the BM and PB, respectively. Comparison of the two groups of MM pts with LTDC (9 CR vs. 17 MGUS-like) showed similar (p>.05) cellular profiles in PB and BM, except for an increased number of BM and PB normal PCs in CR patients (P≤.04). Consequently, for all subsequent analyses, LTDC myeloma pts were pooled together. When compared to HA, patients with LTDC had increased numbers of CD8 T-cells and CD56dim NK-cells in both the BM and PB (p≤.03 and p≤.01, respectively). Despite this, the distribution of BM and PB CD4, CD8 and γδ T-cells among LTDC patients was similar (p>.05) to that of both newly-diagnosed MM and MGUS cases; in contrast, BM and PB Tregs were significantly decreased vs newly-diagnosed MM (P=.03) and MGUS (P=.04). Regarding B-cells and normal PCs, LTDC patients showed increased numbers of BM B-cell precursors (both Pro-B and Pre-B cells) and normal PCs vs. newly diagnosed MM (P≤.05), but not MGUS, together with increased numbers of naïve B-cells vs. both MM and MGUS pts (P≤.01); all such cell populations returned to levels similar (p>.05) to those of HA. As expected, this also included the number of CD34+ B-cell HPC which was increased among patients who achieved LTDC vs MM (p=.02), at levels similar (p>.05) to those of MGUS and HA. Regarding DC, LTDC patients showed normal DC numbers in PB (but with higher PB myeloid-DC numbers vs. MM; p=.02), in association with decreased numbers of plasmacytoid DC and increased monocytic-DC in the BM vs. HA (p≤.04). No differences were found for the numbers of BM and PB monocytes. In summary, here we investigated for the first time the immune cell profile of MM patients who achieve long-term disease control. Our results show that, as newly-diagnosed MM, patients that achieve long-term disease control also show increased numbers of cytotoxic T-cells and CD56dim NK-cells; however, in contrast to newly-diagnosed MM, among LTDC patients such increase is associated with lower numbers of T-regs and an almost complete recovery of the normal PC, B-cell precursor and naïve B-cell compartments both in BM and PB. Further investigations on the activation and functional status of these cell populations are warranted.MO (%)/SP (cels./μl)HA N= 10MGUS N= 23MM N= 16LTDC-MM N= 26T cells9.588110.6117313113711926    CD4+4.85004.6624^6*5085463    CD8+3.7∼216∼4.63865.32645.3431    TCR γδ.2426.3230.2428.3421    Treg.4137.4141^.54*38.3432NK cells.7∼87∼1.51982.11721.6212    CD56 dim.65∼79∼1.41922.21681.6202B cells2.81471.8104.97*68*1.9160    Pro B.11—.06—.02*—.07—    Pre B.6—.4—.08—.23—    Naive SP—80—57^—36*—118    Normal-PCS.18.9.11.7.008.72*.11.84DCs.3449.3653.6848.558    Monocytes2.22472.42853.43023.1315    m-DC SP—11—14—8*—12    MO-DC.11∼29.2036.434.2837    p-DC.2∼4.1.145.112.8.123.8CD34+.9∼1.46.61.1.261.4.431.4    Mie-HPC.8∼—.53—.26—.36—    Linfo-HPC.1—.07—.03*—.05—*p≤.05 LTDC vs MM: ^ p≤.05 LTDC vs MGUS; ∼ p≤.05 LTDC vs HA Disclosures: Paiva: Jansen-Cillag: Honoraria; Celgene: Honoraria. Martinez:Janssen: Honoraria; Celgene: Honoraria. Maiolino:Centocor Ortho Biotech Research & Development: Research Funding.

scholarly journals The histocompatibility restrictions on macrophage T-helper cell interaction determine the histocompatibility restrictions on T-helper cell B-cell interaction.

1978 ◽  
Vol 148 (5) ◽  
pp. 1171-1185 ◽  
Author(s):  
U Yamashita ◽  
E M Shevach
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Interaction ◽  
T Helper Cell ◽  
Helper T Cells ◽  
T Helper ◽  
Ia Antigens ◽  
Nominal Antigen

To study the histocompatibility restriction between macrophages and helper T cells, carrier primed guinea pig T cells were positively selected in vitro with antigenpulsed macrophages for 7 days and the selected T cells were then mixed with hapten-primed B cells and stimulated with antigen in a modified Mishell-Dutton system. Helper T cells could only be selected with syngeneic, but not allogeneic, antigen-pulsed macrophages and would then collaborate only with syngeneic, but not allogeneic, hapten-primed spleen cells. When F1 T cells were selected with antigen-pulsed parental macrophages they would only collaborate with B cells of the same parental strain as the macrophages used in the selection culture. These results are strongly in support of the view that the primed T cell is activated by carrier determinants of the nominal antigen in association with Ia antigens on macrophages and the helper T cell, in turn, activates B cells which bear the same Ia antigens and determinants of the nominal antigen bound to immunoglobulin receptors on their surface. In addition, in experiments with antigens the response to which is controlled by I-linked genes, we demonstrated that primed (responder X nonresponder)F1 T cells would only collaborate with B cells of the responder parent. The defect appeared to be at the level of the B cell in that the addition to the cultures of antigen-presenting cells of the responder type did not restore the ability of F1 T cells to collaborate with non-responder B cells.

scholarly journals Activated B cells express receptors for, and proliferate in response to, pure interleukin 2.

1984 ◽  
Vol 160 (4) ◽  
pp. 1170-1183 ◽  
Author(s):  
R H Zubler ◽  
J W Lowenthal ◽  
F Erard ◽  
N Hashimoto ◽  
R Devos ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Interleukin 2 ◽  
T Helper ◽  
Spleen Cells ◽  
Human Spleen ◽  
Apparent Dissociation Constant ◽  
Activated B Cells

In this study we investigated whether interleukin 2 (IL-2) acts on B cell proliferation and whether activated B cells express IL-2 receptors. First, the functional activity of immunoaffinity-purified or recombinant human IL-2 was studied in a B blast assay using positively selected murine surface Ig-positive cells that had been activated by lipopolysaccharide (LPS) plus anti-Ig antibodies (anti-Ig). In this assay, T cells were not detected by fluorescence-activated cell sorter analysis. It was found that both IL-2 preparations led to optimal B cell proliferation compared with supernatants obtained from murine or human spleen cells or murine cloned T helper cells. Second, we observed that the IL-2 requirement in this assay was about the same as in a proliferation assay using lectin-activated polyclonal murine Lyt-2-positive T cells. Third, analysis of the binding of radiolabeled immunoaffinity-purified IL-2 to B cells indicated that LPS plus anti-Ig-activated B cells expressed a mean of 3,500 IL-2 receptors per cell with an apparent dissociation constant of 150 pM. However, neither nonactivated B cells nor B cells activated by LPS alone exhibited significant specific IL-2 binding. The functional and the receptor data are consistent with the conclusion that IL-2 is a growth factor not only for T cells but also for B cells.

scholarly journals Mathematical model of a personalized neoantigen cancer vaccine and the human immune system

2021 ◽  
Vol 17 (9) ◽  
pp. e1009318
Author(s):  
Marisabel Rodriguez Messan ◽  
Osman N. Yogurtcu ◽  
Joseph R. McGill ◽  
Ujwani Nukala ◽  
Zuben E. Sauna ◽  
...  
Keyword(s):  
Mathematical Model ◽  
T Cells ◽  
Immune System ◽  
Immune Responses ◽  
Cancer Vaccine ◽  
Tumor Size ◽  
Cancer Vaccines ◽  
Patient Specific ◽  
Human Immune System ◽  
Human Immune

Cancer vaccines are an important component of the cancer immunotherapy toolkit enhancing immune response to malignant cells by activating CD4+ and CD8+ T cells. Multiple successful clinical applications of cancer vaccines have shown good safety and efficacy. Despite the notable progress, significant challenges remain in obtaining consistent immune responses across heterogeneous patient populations, as well as various cancers. We present a mechanistic mathematical model describing key interactions of a personalized neoantigen cancer vaccine with an individual patient’s immune system. Specifically, the model considers the vaccine concentration of tumor-specific antigen peptides and adjuvant, the patient’s major histocompatibility complexes I and II copy numbers, tumor size, T cells, and antigen presenting cells. We parametrized the model using patient-specific data from a clinical study in which individualized cancer vaccines were used to treat six melanoma patients. Model simulations predicted both immune responses, represented by T cell counts, to the vaccine as well as clinical outcome (determined as change of tumor size). This model, although complex, can be used to describe, simulate, and predict the behavior of the human immune system to a personalized cancer vaccine.

scholarly journals SARS-COV-2 acts as a test of Air Pollution, Lifestyle Disorders and Immune Tolerance dysregulation in human body

2021 ◽  
Author(s):  
bose Karthik
Keyword(s):  
Immune System ◽  
Immune Tolerance ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Human Immune System ◽  
Adaptive Immune ◽  
Human Immune ◽  
Humoral Responses ◽  
Skeletal Mechanism ◽  
Insight Into

SARS-COV-2 is reported to be associated with severe immune dysregulation, delayed humoral responses and accelerated innate immune response mediated damages. As the pandemic is turning the world upside down, In order to address this disease we should first get an insight into the mechanism of action through which SARS-COV-2 is achieving the above said dysregulating or modulating effects on human immune system. T his article presents the basic or skeletal mechanism through which SARS-COV-2 dysregulates immune system by targeting innate immune system, adaptive immune system and different immune tolerance check points by dysregulating different miRNA’s and the preexisting conditions or comorbidities of the patients. This article comprises of the comparative and comprehensive literature review targeting all topics with the data available/reported till date in the scientific community.

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