Adoptive immunotherapy of a BALB/c lymphoma by syngeneic anti-DBA/2 immune lymphoid cells: Characterization of the effector population and evidence for the role of the host's non-T cells

Fc fragments derived from human immunoglobulin were found to be capable of inducing both a proliferative and polyclonal antibody response in human peripheral blood lymphocyte cultures. The cell population proliferating in response to Fc fragments belongs to the B cell lineage. Expression of polyclonal antibody formation requires the presence of both adherent monocytes and T cells. The role of the monocyte is to enzymatically cleave the Fc fragment into 19,000 mol wt Fc subfragments that are then able to induce polyclonal antibody secretion. Stimulation of polyclonal antibody production by Fc subfragments occurs in the absence of adherent monocytes but still requires the presence of T cells.

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Generation and Characterization Of a CD30 Positive T-Cell Lymphoma Mouse Model Resembling Human Anaplastic Large Cell Lymphoma

Blood ◽

10.1182/blood.v122.21.2450.2450 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2450-2450

Author(s):

Cathrin Klingeberg ◽

Anna Lena Illert ◽

Nicolas Schneider ◽

Christian Peschel ◽

Cornelius Miething ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Large Cell ◽

Cre Recombinase ◽

Double Negative ◽

Ki 67 ◽

The Impact

Abstract Anaplastic large cell lymphomas (ALCL) are a subgroup of aggressive Non-Hodgkin-Lymphomas mainly affecting children and young adults. In 60 % of systemic ALCLs, a translocation t(2;5) (p23;q35) resulting in NPM-ALK fusion gene expression is found. The constitutively activation of ALK tyrosine kinase expressed from the NPM-promoter causes increased proliferation and inhibition of apoptosis thereby promoting cell survival and tumorigenesis. Immunphenotypic characterization of human ALCLs revealed highly CD30-positive cells of T- or Null-Cell-origin and resulted in promising clinical trials with CD30-coupled antibodies. However, the impact of CD30 on diseases development as well as NPM-ALK signal transduction in course of disease remains unclear and appropriate mouse models to answer these questions are missing. In this regard, we established a retroviral murine bone marrow (BM) transplantation model resembling a human ALCL-like T-cell neoplasia. Therefore we use an inducible Cre/loxP system where NPM-ALK expression is controlled and expressed in a special type of early T-cells. For generation of this vector, we inserted a floxed translational ‘stop-cassette’ between the retroviral promoter MSCV-LTR and the NPM-ALK cDNA, which guaranties specific expression of NPM-ALK only in cells, where the enzyme Cre-recombinase is expressed. Recognition of the loxP-sites by Cre-recombinase leads in our system to deletion of the stop-cassette and consequently NPM-ALK expression. Using different Cre-expressing cell types allowed us to study pathogenesis of ALCL in more detail. In our recent study, we infected bone marrow of transgenic mice expressing Cre-recombinase under the control of the Lck-promotor with our MSCV-Stop-NPM-ALK-IRES-EGFP (MSNAIE) vector and transplanted it into lethally irradiated C57Bl6 recipient mice. With a latency of 4-5 months, these mice developed Thy1.2-positive lymphomas and died from neoplastic infiltration of bone marrow and lymphatic organs with T-cells. Immunphenotypic analyses confirmed T-Cell origin of the lymphomas and showed importantly highly CD30-expression. Staining of the different T-cell-subpopulations demonstrated highest NPM-ALK expression in immature CD4/CD8 double negative T-cells and not fully differentiated CD4/CD8 double positive T-cells. Interestingly, FACS-staining of the proliferation marker Ki-67 revealed highest expression in CD4/CD8 double negative T-cells, in contrast to the other subpopulations where Ki-67 is less detected. Therefore we hypothesized, that the lymphoma initiating cell (LIC) must be within this early T-cell population. Most interestingly we found highest CD30-expression just in the same CD4/CD8 negative T-cell population, pointing to a crucial role of CD30 in lymphoma initiation. To further substantiate our hypothesis we performed secondary and tertiary transplantations with different sorted T-Cell subpopulation and indeed, the immature CD4/CD8 double negative population was able to initiate lymphoma growth in recipient mice. Further transplantations by limited dilution will help to identify the leukemia initiating cell in this model. Taken together, our murine LckCre-NPM-ALK bone marrow transplantation model represents a precise and versatile tool to study disease initiation and development resembling human ALCL. Moreover, the impact of specific proteins (e.g. CD30) in the course of disease can be addressed by combining Knockout (e.g. CD30)/LckCre transgenic mice with our model. To this end we crossed CD30/Lck-Cre mice, and preliminary analysis indicate that CD30 expression seems not to be required for the initial onset of disease. Further characterization of the role of CD30 in ALCL is ongoing. Disclosures: No relevant conflicts of interest to declare.

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Characterization of intact proviruses in blood and lymph node from HIV-infected individuals undergoing analytical treatment interruption

10.1101/456020 ◽

2018 ◽

Cited By ~ 2

Author(s):

Line K. Vibholm ◽

Julio C.C. Lorenzi ◽

Joy A. Pai ◽

Yehuda Z. Cohen ◽

Thiago Y. Oliveira ◽

...

Keyword(s):

T Cells ◽

Lymph Node ◽

Antiretroviral Therapy ◽

Treatment Interruption ◽

Latent Reservoir ◽

Lymphoid Tissues ◽

Analytical Treatment ◽

Hiv 1

AbstractThe role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near full-length (NFL) proviral DNA, and env from viral outgrowth cultures (VOAs). 5 HIV-1 infected individuals on antiretroviral therapy (ART) were studied, 4 of whom participated in a clinical trial that included an analytical treatment interruption. Intact or replication competent clonal sequences from blood and lymph node overlapped. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the 4 individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggests that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia.

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Cell surface characterization of malignant T cells from lymphoblastic lymphoma using monoclonal antibodies: evidence for phenotypic differences between malignant T cells from patients with acute lymphoblastic leukemia and lymphoblastic lymphoma

Blood ◽

10.1182/blood.v57.6.1105.bloodjournal5761105 ◽

1981 ◽

Vol 57 (6) ◽

pp. 1105-1110 ◽

Cited By ~ 1

Author(s):

A Bernard ◽

L Boumsell ◽

EL Reinherz ◽

LM Nadler ◽

J Ritz ◽

...

Keyword(s):

T Cells ◽

Monoclonal Antibodies ◽

Acute Lymphoblastic Leukemia ◽

Surface Characterization ◽

Lymphoblastic Leukemia ◽

Lymphoblastic Lymphoma ◽

Lymphoid Cells ◽

Phenotypic Differences ◽

Malignant T Cells

A series of monoclonal antibodies was used for the characterization of malignant T cells from 21 patients with lymphoblastic lymphoma (LL). The tumor population from these patients showed a marked degree of phenotypic heterogeneity and a proportion (one-third) of patients had tumor cells that did not conform exactly with the cells normally detected in the thymus. However, these cell populations could be related to the early or common or late thymocyte population (about one- third of the patients in each category). This contrast, with the characterization of malignant T cells from 43 patients with acute lymphoblastic leukemia (ALL) that could be related to either early or common thymocytes, with an exception of two patients categorized as having a tumor population related to late thymocytes. Further phenotypic differences between cells from ALL and LL could be demonstrated by investigation with two additional monoclonal antibodies, A50 and U4. Among patients with malignant T cells related to common thymocyte, 0/12 patients with ALL had cells recognized by A50, where 5/8 patients with LL had A50+ cells. Among patients with early thymocytes, only patients with ALL had cells recognized by U4. In addition, 5 LL patients had cells reactive with J5, a monoclonal antibody recognizing the common ALL antigen (CALLA). Since CALLA was found on cells related to common and late thymocytes, CALLA is neither lineage specific, nor can it be viewed as being peculiar to malignant lymphoid cells arrested at very immature stages of differentiation.

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Abstract 641: The Role of Interleukin-23 in the Development of Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.641 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Aliia Fatkhullina ◽

Iuliia Peshkova ◽

Ekaterina Koltsova

Keyword(s):

T Cells ◽

Cell Function ◽

Inflammatory Diseases ◽

Myeloid Cells ◽

Myeloid Cell ◽

Chronic Inflammatory Disease ◽

Lymphoid Cells ◽

Efficient Manner ◽

Mediators Of Inflammation

Atherosclerosis is lipid-driven chronic inflammatory disease of the arterial wall mediated by innate and adaptive immune responses. Inflammation promotes the development atherosclerotic plaques. Cytokines are soluble mediators of inflammation and important players in the pathogenesis of atherosclerosis. IL-23, a cytokine of IL-6/IL-12 cytokines superfamily is produced by myeloid cells and regulates the production of IL-17 and IL-22 by T helper IL-17 producing (Th17) cells, innate lymphoid cells of type 3 (ILC3) and gamma delta T cells in various auto-inflammatory diseases. IL-23R expression was also detected on myeloid cells but its role in regulation of myeloid cell function is not well defined. The level of IL-23 was shown to be upregulated in cardiovascular pathologies. Therefore, we decided to address the role of IL-23 in atherosclerosis using Il23p19 and Il23(R) receptor deficient mice. Surprisingly, atherosclerosis prone, Ldlr -/- mice transplanted with Il23p19 -/- or Il23r -/- bone marrow and fed with Western diet (WD) for 14 weeks demonstrated acceleration of atherosclerosis progression, which was characterized by increased accumulation of various hematopoietic cells in the aortas. Analysis of cytokine production unexpectedly revealed no changes in IL-17A and IFN-gamma production among CD4 T cells in the aortas. This effect was specific to aortas, as IL-17A production in the intestine of Il23p19 -/- mice was reduced, similarly to previously published observations. On the other hand, macrophages from Il23p19 -/- mice were able to uptake oxLDL in more efficient manner compared to wt controls, suggesting the regulatory role of IL-23 in foam cells formation. We also found enhanced inflammatory gene expression in aortas of Il23p19 -/- -> Ldlr -/- and Il23r -/- -> Ldlr -/- mice compared to wt controls. Overall our data suggest IL-17 independent atheroprotective role of IL-23.

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Characterization of pathogenic CD8 + T cells in Chlamydia - infected OT1 mice

Infection and Immunity ◽

10.1128/iai.00453-21 ◽

2021 ◽

Author(s):

Zengzi Zhou ◽

Qi Tian ◽

Luying Wang ◽

Xin Sun ◽

Nu Zhang ◽

...

Keyword(s):

T Cells ◽

Chlamydia Trachomatis ◽

Cd8 T Cells ◽

Chlamydial Infection ◽

Critical Role ◽

Wild Type ◽

Chlamydia Muridarum ◽

Time Of Infection

Chlamydia trachomatis is a leading infectious cause of infertility in women due to its induction of lasting pathology such as hydrosalpinx. Chlamydia muridarum induces mouse hydrosalpinx because C. muridarum can both invade tubal epithelia directly (as a 1 st hit) and induce lymphocytes to promote hydrosalpinx indirectly (as a 2 nd hit). In the current study, a critical role of CD8 + T cells in chlamydial induction of hydrosalpinx was validated in both wild type C57BL/6J and OT1 transgenic mice. OT1 mice failed to develop hydrosalpinx partially due to the failure of their lymphocytes to recognize chlamydial antigens. CD8 + T cells from naïve C57BL/6J rescued the recipient OT1 mice to develop hydrosalpinx when naïve CD8 + T cells were transferred at the time of infection with Chlamydia . However, when the transfer was delayed for 2 weeks or longer after the chlamydial infection, naïve CD8 + T cells no longer promoted hydrosalpinx. Nevertheless, Chlamydia -immunized CD8 + T cells still promoted significant hydrosalpinx in the recipient OT1 mice even when the transfer was delayed for 3 weeks. Thus, CD8 + T cells must be primed within 2 weeks after chlamydial infection to be pathogenic but once primed, they can promote hydrosalpinx for >3 weeks. However, Chlamydia -primed CD4 + T cells failed to promote chlamydial induction of pathology in OT1 mice. This study has optimized an OT1 mouse-based model for revealing the pathogenic mechanisms of Chlamydia -specific CD8 + T cells.

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The Role of IL-17 and Related Cytokines in Inflammatory Autoimmune Diseases

Mediators of Inflammation ◽

10.1155/2017/3908061 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 128

Author(s):

Taku Kuwabara ◽

Fumio Ishikawa ◽

Motonari Kondo ◽

Terutaka Kakiuchi

Keyword(s):

T Cells ◽

Autoimmune Diseases ◽

Chronic Inflammation ◽

Th17 Cells ◽

Lymphoid Cells ◽

Interleukin 17 ◽

Human Rheumatoid Arthritis ◽

Functional Understanding ◽

Bacteria And Fungi

Interleukin-17 (IL-17) induces the production of granulocyte colony-stimulating factor (G-CSF) and chemokines such as CXCL1 and CXCL2 and is a cytokine that acts as an inflammation mediator. During infection, IL-17 is needed to eliminate extracellular bacteria and fungi, by inducing antimicrobial peptides such as defensin. This cytokine also plays an important role in chronic inflammation that occurs during the pathogenesis of autoimmune diseases and allergies such as human rheumatoid arthritis (RA) for which a mouse model of collagen-induced arthritis (CIA) is available. In autoimmune diseases such as RA and multiple sclerosis (MS), IL-17 is produced by helper T (Th) cells that are stimulated by IL-1βand IL-6 derived from phagocytes such as macrophages and from tissue cells. IL-17 contributes to various lesions that are produced by Th17 cells, one subset of helper T cells, and byγδT cells and innate lymphoid cells. It strongly contributes to autoimmune diseases that are accompanied by chronic inflammation. Thus, a functional understanding of Th17 cells is extremely important. In this review, we highlight the roles of cytokines that promote the development and maintenance of pathogenic Th17 cells in autoimmune diseases.

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Regulatory effects of mast cells on lymphoid cells: The role of histamine type 1 receptors in the interaction between mast cells, helper T cells and natural suppressor cells

Cellular Immunology ◽

10.1016/0008-8749(86)90066-3 ◽

1986 ◽

Vol 103 (1) ◽

pp. 41-53 ◽

Cited By ~ 16

Author(s):

Manzoor M. Khan ◽

Samuel Strober ◽

Kenneth L. Melmon

Keyword(s):

T Cells ◽

Mast Cells ◽

Suppressor Cells ◽

Lymphoid Cells ◽

Helper T Cells ◽

Natural Suppressor Cells ◽

Regulatory Effects

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Characterization of Mitochondrial Bioenergetics in Preeclampsia

Journal of Clinical Medicine ◽

10.3390/jcm10215063 ◽

2021 ◽

Vol 10 (21) ◽

pp. 5063

Author(s):

Ramana Vaka ◽

Evangeline Deer ◽

Mark Cunningham ◽

Kristen M. McMaster ◽

Kedra Wallace ◽

...

Keyword(s):

Oxidative Stress ◽

T Cells ◽

Cd4 T Cells ◽

Type I ◽

Pregnant Rats ◽

Complex Iv ◽

Tnf Α ◽

Placental Ischemia

Preeclampsia (PE) is characterized by new onset hypertension during pregnancy and is associated with oxidative stress, placental ischemia, and autoantibodies to the angiotensin II type I receptor (AT1-AA). Mitochondrial (mt) dysfunction in PE and various sources of oxidative stress, such as monocytes, neutrophils, and CD4 + T cells, have been identified as important players in the pathophysiology of PE. We have established the significance of AT1-AA, TNF-α, and CD4 + T cells in causing mitochondrial (mt) dysfunction in renal and placental tissues in pregnant rats. Although the role of mt dysfunction from freshly isolated intact placental mitochondria has been compared in human PE and normally pregnant (NP) controls, variations among preterm PE or term PE have not been compared and mechanisms contributing to mt ROS during PE are unclear. Therefore, we hypothesized PE placentas would exhibit impaired placental mt function, which would be worse in preterm PE patients than in those of later gestational ages. Immediately after delivery, PE and NP patient’s placentas were collected, mt were isolated and mt respiration and ROS were measured. PE patients at either < or >34 weeks gestational age (GA) exhibited elevated blood pressure and decreased placental mt respiration rates (state 3 and maximal). Patients delivering at >34 weeks exhibited decreased Complex IV activity and expression. Placental mtROS was significantly reduced in both PE groups, compared to NP placental mitochondria. Collectively, the study demonstrates that PE mt dysfunction occurs in the placenta, with mtROS being lower than that seen in NP controls. These data indicate why antioxidants, as a potential target or new therapeutic agent, may not be ideal in treating the oxidative stress associated with PE.

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