30 results
Search Results
2. Delineation of two defects responsible for T-cell hyporesponsiveness to concanavalin A in MRL congenic mice.
- Author
-
Cameron, R. and Waterfield, J. D.
- Subjects
T cells ,IMMUNOGLOBULINS ,CELL proliferation ,MICE ,GENETICS ,CYTOLOGY - Abstract
MRL-lpr mice and their congenic counterparts MRL- + spontaneously develop an autoimmune disease that resembles systemic lupus erythematosus in humans. The two strains, although congenic, differ by a considerable number of disease parameters, reflecting the expression of the lpr autosomal recessive gene. One paradox that has developed out of the work utilizing the congenic mice is that the gene responsible for lymphoproliferation also appears to be responsible for the inability of T cells to respond to proliferative signals in vitro. In this paper we investigated a possible lpr gene-encoded macrophage defect in these mice. It was found, however, that both the MRL- + and MRL-lpr mice failed to divide in response to Con A, the lack of division correlating with an inability to secrete the growth promoter interleukin-2. In MRL- + mice and young MRL-lpr mice this non-responsiveness was corrected by the addition of normal CRA PEC. The defect could not be explained by a failure of M RL- + or M RL-lpr peritoneal exudate cells to quantitatively or qualitatively provide a source of interleukin-1 to Con A-activated T cells or by the possibility that the peritoneal exudate cells were blocked in their function by the presence of sera-derived autoantibodies and/or immune complexes on their membranes. We postulate that the inability of T cells to proliferate in MRL congenic mice can be explained by two defects: (i) the failure of antigen-presenting cells in MRL- + and MRL-lpr to provide the necessary signals to immunocompetent T cells, this defect not being associated with the lpr gene, and (ii) the lpr gene controlled outgrowth of a unique T-cell population that cannot respond in our assay system. [ABSTRACT FROM AUTHOR]
- Published
- 1986
3. <em>In vitro</em> responses to the liver antigen F.
- Author
-
Sunshine, G.H., Cyrus, Muriel, and Winchester, Guil
- Subjects
ANTIGENS ,LIVER ,AUTOIMMUNITY ,CELL proliferation ,T cells ,IMMUNOGLOBULINS - Abstract
In this paper we describe the first in vitro response to the liver alloantigen F. The anti-F response serves as a valuable model for autoimmune phenomena since priming appropriate strains of mice (responders) with allogeneic but not syngeneic type F leads to autoantibody production. The in vitro system is based on the proliferation of T cells, from mice primed in vivo with F, when coincubated with splenic adherent cells (SAC) prepulsed with F in vivo. The system displays two important correlates of the in vivo antibody response to F:1.T cells from mice primed with syngeneic F do not proliferate when incubated with SAC prepulsed with syngeneic F and 2. Mice that do not make antibody responses to allo F in vivo (DBA/2) do not show in vitro proliferative responses. These findings indicate that the proliferative assay is a good in vitro model for the F response. [ABSTRACT FROM AUTHOR]
- Published
- 1982
4. Follicular Helper T Cell Derived Exosomes Promote B Cell Proliferation and Differentiation in Antibody-Mediated Rejection after Renal Transplantation.
- Author
-
Yang, Jintao, Bi, Lili, He, Xiuyun, Wang, Zhen, Qian, Yeyong, Xiao, Li, and Shi, Bingyi
- Subjects
CELL proliferation ,B cells ,BLOOD collection ,CELL physiology ,CELLULAR immunity ,GENE expression ,GRAFT rejection ,IMMUNOGLOBULINS ,KIDNEY transplantation ,T cells ,HLA-B27 antigen ,EXOSOMES - Abstract
Follicular helper T cells (Tfh cells) are closely related to the occurrence and development of antibody-mediated rejection (AMR) after renal transplantation. Exosomes play a key role in the rejection after organ transplantation. However, whether Tfh-derived exosomes are involved in AMR has not been reported. We collected peripheral blood from 42 kidney transplant patients and found no significant differences in CD4+CXCR5+ and CD4+CXCR5+CXCR3+CCR6-exosomes between AMR and non-AMR groups, whereas the proportion of CD4+CXCR5+CXCR3-exosomes was significantly higher in AMR group than that in non-AMR group; CTLA-4 expression of CD4+CXCR5+exosomes was significantly lower in AMR group than that in non-AMR group. HLA-G expression was not significantly different between two groups. We further separated CD4+CXCR5+cells from patients by magnetic beads. Coculture experiments showed that Tfh cell-derived exosomes in AMR patients significantly promoted B cell proliferation and differentiation, compared with non-AMR group, the percentage of B cells and plasma cells increased by 87.52% and 110.2%, respectively. In conclusion, our study found that Tfh cell-derived exosomes could promote the proliferation and differentiation of B cells and they may play an important role in the development of AMR after renal transplantation. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
5. Use of In Vitro Assays to Assess Immunogenicity Risk of Antibody-Based Biotherapeutics.
- Author
-
Joubert, Marisa K., Deshpande, Meghana, Yang, Jane, Reynolds, Helen, Bryson, Christine, Fogg, Mark, Baker, Matthew P., Herskovitz, Jonathan, Goletz, Theresa J., Zhou, Lei, Moxness, Michael, Flynn, Gregory C., Narhi, Linda O., and Jawa, Vibha
- Subjects
BIOTHERAPY ,IMMUNOGLOBULINS ,MONONUCLEAR leukocytes ,T cells ,CELL proliferation - Abstract
An In Vitro Comparative Immunogenicity Assessment (IVCIA) assay was evaluated as a tool for predicting the potential relative immunogenicity of biotherapeutic attributes. Peripheral blood mononuclear cells from up to 50 healthy naïve human donors were monitored up to 8 days for T-cell proliferation, the number of IL-2 or IFN-γ secreting cells, and the concentration of a panel of secreted cytokines. The response in the assay to 10 monoclonal antibodies was found to be in agreement with the clinical immunogenicity, suggesting that the assay might be applied to immunogenicity risk assessment of antibody biotherapeutic attributes. However, the response in the assay is a measure of T-cell functional activity and the alignment with clinical immunogenicity depends on several other factors. The assay was sensitive to sequence variants and could differentiate single point mutations of the same biotherapeutic. Nine mAbs that were highly aggregated by stirring induced a higher response in the assay than the original mAbs before stirring stress, in a manner that did not match the relative T-cell response of the original mAbs. In contrast, mAbs that were glycated by different sugars (galactose, glucose, and mannose) showed little to no increase in response in the assay above the response to the original mAbs before glycation treatment. The assay was also used successfully to assess similarity between multiple lots of the same mAb, both from the same manufacturer and from different manufacturers (biosimilars). A strategy for using the IVCIA assay for immunogenicity risk assessment during the entire lifespan development of biopharmaceuticals is proposed. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
6. Homeostatic 'bystander' proliferation of human peripheral blood B cells in response to polyclonal T-cell stimulation in vitro.
- Author
-
Jasiulewicz, Aleksandra, Lisowska, Katarzyna A., Pietruczuk, Krzysztof, Frąckowiak, Joanna, Fulop, Tamas, and Witkowski, Jacek M.
- Subjects
CELL proliferation ,B cells ,T cells ,IMMUNOGLOBULINS ,CONCANAVALIN A - Abstract
The mechanisms of maintenance of adequate numbers of B lymphocytes and of protective levels of immunoglobulins in the absence of antigenic (re)stimulation remain not fully understood. Meanwhile, our results presented here show that both peripheral blood naive and memory B cells can be activated strongly and non-specifically (in a mitogen-like fashion) in 5-day in vitro cultures of anti-CD3- or concanavalin A (Con A)-stimulated peripheral blood mononuclear cells of healthy people. This polyclonal, bystander activation of the B cells includes multiple divisions of most of them (assessed here by the flow cytometric technique of dividing cell tracking) and significant antibody [immunoglobulin M (IgM) and IgG] secretion. Observed proliferation of the CD19
+ B cells depends on contact with stimulated T helper (Th ) cells (via CD40-CD40L interaction) and on the response of B cells to secreted interleukins IL-5, IL-10 and IL-4, and is correlated with the levels of these Th -derived molecules, while it does not involve the ligation of the BCR/CD19 complex. We suggest that the effect might reflect the situation occurring in vivo as the homeostatic proliferation of otherwise non-stimulated, peripheral B lymphocytes, providing an always ready pool for efficient antibody production to any new (or cognate) antigen challenge. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
7. Expression of plasma cell alloantigen 1 defines layered development of B-1a B-cell subsets with distinct innate-like functions.
- Author
-
Hongsheng Wang, Dong-Mi Shin, Abbasi, Sadia, Jain, Shweta, Kovalchuk, Alexander L., Beaty, Natalie, Chen, Sophia, Gonzalez-Garcia, Ines, and Morse III, Herbert C.
- Subjects
PLASMA cells ,B cells ,GENE expression ,IMMUNOGLOBULINS ,CELL differentiation ,T cells ,CELL proliferation - Abstract
Innate-like B-1a cells contribute significantly to circulating natural antibodies and mucosal immunity as well as to immunoregulation. Here we show that these classic functions of B-1a cells segregate between two unique subsets defined by expression of plasma cell alloantigen 1 (PC1), also known as ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1). These subsets, designated B-1a. PC1
lo and B-1a.PC1hi , differ significantly in IgH chain utilization. Adoptively transferred PC1lo cells secreted significantly more circulating natural IgM and intestinal IgA than PC1hi cells. In contrast, PC1hi cells produced more IL-10 than PC1lo cells when stimulated with LPS and phorbol 12-myristate 13-acetate (PMA). PC1hi cells were also more efficient than PC1lo cells in regulating Th1 cell differentiation, even though both B-1a subsets were comparably active in stimulating T-cell proliferation. Furthermore, PC1lo cells generated antigen-specific IgM responses to pneumococcal polysaccharide antigens, whereas PC1hi cells do not. We found that PC1hi cells develop from an early wave of B-1a progenitors in fetal life, whereas ~ cells are generated from a later wave afterbirth. We conclude that identification of B-1a.PC1lo and B-1a.PC1hi cells extends the concept of a layered immune system with important implications for developing effective vaccines and promoting the generation of immunoregulatory B cells. [ABSTRACT FROM AUTHOR]- Published
- 2012
- Full Text
- View/download PDF
8. Toward a molecular understanding of adaptive immunity: a chronology - part II.
- Author
-
Smith, Kendall A.
- Subjects
T cells ,CELL proliferation ,IMMUNOGLOBULINS ,ANTIGENS ,INTERLEUKIN receptors - Abstract
By 1980 it was obvious that to more fully understand adaptive immunity, one needed to somehow reduce the tremendous complexity of antigen recognition byT cell populations. Thus, there were two developments that resulted in a paradigm shift in immunology, one being the generation of monoclonal antibodies (MoAbs), and the other the development of monoclonal functional antigen-specific T cell lines. For the first time, the cellular reagents became available to ask new questions as to how individual cells comprising the complex cell populations recognize and respond to changes in their molecular environments. The first successful generation of monoclonal T cells depended upon the understanding that antigen renders cells responsive to the antigen non-specificT cell growth factor that came to be termed interleukin-2 (IL-2), which could then be used in propagating large numbers of the progeny of single cells, which in turn could then be used for molecular analyses. Monoclonal functional human T cells were used to immunize mice to generate clone-specific (clonotypic) MoAbs, which then permitted the first biochemical characterizations of the antigen recognition elements of theT cell antigen receptor (TCR) complex. Moreover, the use of monoclonal cytolytic and helper/inducer humanT cell clones essentially proved that theT cell-specific moleculesT4 (CD4) andT8 (CD8) functioned as accessory molecules in antigen recognition by defining MHC class II or class I restriction respectively. As well, the expression of the T3 (CD3) molecules, found to be common to all T cells, were shown further to be obligatory for functional antigen-specificT cell signaling.The monoclonal IL-2-dependent T cells were also instrumental in the isolation and purification of the IL-2 molecule to homogeneity, the first interleukin molecule to be identified and characterized. These advances then led to the generation of pure radiolabeled IL-2 molecules that were used to identify the first interleukin cellular receptors, and as well the generation of the first MoAbs reactive with both IL-2 and IL-2 receptors. All of these advances led subsequently to the isolation of the first cDNA clones recognizing one of the two chains comprising theT cell antigen recognition elements (β-chain), as well cDNA clones encoding IL-2. Accordingly, armed with all of these unique cellular and molecular reagents, it was possible to determine that antigen triggering of theTCR complex initiates IL-2 production and IL-2 receptor expression, which in turn initiate theT cell clonal proliferative expansion, envisioned by Burnet in his formulation of the clonal selection theory.Thus, adaptive immunity receives antigen-specific activation signals from the environment and turns them into antigen non-specific endogenous action signals. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
9. Homeostatic Proliferation Fails to Efficiently Reactivate HIV-1 Latently Infected Central Memory CD4+ T Cells.
- Author
-
Bosque, Alberto, Famiglietti, Marylinda, Weyrich, Andrew S., Goulston, Claudia, and Planelles, Vicente
- Subjects
HOMEOSTASIS ,T cells ,CELL proliferation ,CELL differentiation ,IMMUNOGLOBULINS ,CELL death - Abstract
Homeostatic proliferation ensures the longevity of central memory T-cells by inducing cell proliferation in the absence of cellular differentiation or activation. This process is governed mainly by IL-7. Central memory T-cells can also be stimulated via engagement of the T-cell receptor, leading to cell proliferation but also activation and differentiation. Using an in vitro model of HIV-1 latency, we have examined in detail the effects of homeostatic proliferation on latently infected central memory T cells. We have also used antigenic stimulation via anti-CD3/anti-CD28 antibodies and established a comparison with a homeostatic proliferation stimulus, to evaluate potential differences in how either treatment affects the dynamics of latent virus populations. First, we show that homeostatic proliferation, as induced by a combination of IL-2 plus IL-7, leads to partial reactivation of latent HIV-1 but is unable to reduce the size of the reservoir in vitro. Second, latently infected cells are able to homeostatically proliferate in the absence of viral reactivation or cell differentiation. These results indicate that IL-2 plus IL-7 may induce a detrimental effect by favoring the maintenance of the latent HIV-1 reservoir. On the other hand, antigenic stimulation efficiently reactivated latent HIV-1 in cultured central memory cells and led to depletion of the latently infected cells via virus-induced cell death. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
10. Lymphocyte Cell-Cycle Inhibition by HLA-G Is Mediated by Phosphatase SHP-2 and Acts on the mTOR Pathway.
- Author
-
Ketroussi, Farah, Giuliani, Massimo, Bahri, Rajia, Azzarone, Bruno, Charpentier, Bernard, and Durrbach, Antoine
- Subjects
LYMPHOCYTES ,CELL cycle ,PHOSPHATASES ,LEUCOCYTES ,ANTIGENS ,T cells ,IMMUNOGLOBULINS ,CELL proliferation - Abstract
Human leukocyte antigen G (HLA-G) is involved in regulating T-cell responses through its interaction with inhibitory receptors belonging to the immunoglobulin-like transcript family (ILT). In this context, we investigated the pathways involved in the control of cell-cycle entry of T cells following HLA-G interaction with its inhibitory receptor. We show that HLA-G acts through its interaction with the LILRB1 receptor expressed on T lymphocytes. Both HLA-G and LILRB1 antibodies block the inhibitory effect of HLA-G and restore T-cell proliferation. The interaction of HLA-G with T lymphocytes is associated with phosphorylation of SHP-2 phosphatase, but not SHP-1. In addition, in activated T cells, their incubation with HLA-G is not associated with a decrease in the TCR or CD28 downstream pathways, but is associated with dephosphorylation of the mTOR molecule and p70S6K. In contrast, Akt, which acts upstream of mTOR, is not affected by HLA-G. The inhibition of SHP-2 by NSC-87877(5 μM), a chemical inhibitor of SHP-2, or the use of siRNA, abrogates dephosphorylation of mTOR and impairs the overexpression of p27
kip in the presence of HLA-G. Together, these results indicate that HLA-G is associated with activation of phosphatase SHP-2, which inhibits the mTOR pathway and favors the inhibition of the cell-cycle entry of human-activated T cells. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
11. Autoimmune regulator (AIRE)-deficient CD8+CD28low regulatory T lymphocytes fail to control experimental colitis.
- Author
-
Pomié, Céline, Vicente, Rita, Vuddamalay, Yirajen, Lundgren, Brita Ardesjö, van der Hoek, Mark, Enault, Geneviève, Kagan, Jérémy, Fazilleau, Nicolas, Scott, Hamish S., Romagnoli, Paola, and van Meerwijk, Joost P. M.
- Subjects
MEDICAL research ,LYMPHOCYTES ,IMMUNOGLOBULINS ,GENOTYPE-environment interaction ,CELL proliferation ,T cells - Abstract
Mutations in the gene encoding the transcription factor autoimmune regulator (AIRE) are responsible for autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome. AIRE directs expression of tissue-restricted antigens in the thymic medulla and in lymph node stromal cells and thereby substantially contributes to induction of immunological tolerance to self-antigens. Data from experimental mouse models showed that AIRE deficiency leads to impaired deletion of autospecific T-cell precursors. However, a potential role for AIRE in the function of regulatory T-cell populations, which are known to play a central role in prevention of immunopathology, has remained elusive. Regulatory T cells of CD8
+ CD28low phenotype efficiently control immune responses in experimental autoimmune and colitis models in mice. Here we show that CD8+ CD28low regulatory T lymphocytes from AIRE-deficient mice are transcriptionally and phenotypically normal and exert efficient suppression of in vitro immune responses, but completely fail to prevent experimental colitis in vivo. Our data therefore demonstrate that AIRE plays an important role in the in vivo function of a naturally occurring regulatory T-cell population. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
12. Functional Memory B Cells and Long-Lived Plasma Cells Are Generated after a Single Plasmodium chabaudi Infection in Mice.
- Author
-
Ndungu, Francis Maina, Cadman, Emma Tamsin, Coulcher, Joshua, Nduati, Eunice, Couper, Elisabeth, MacDonald, Douglas William, Ng, Dorothy, and Langhorne, Jean
- Subjects
IMMUNOGLOBULINS ,PLASMODIUM genetics ,B cells ,CELL proliferation ,PLASMA cells ,T cells ,IMMUNE response ,PHYSIOLOGY - Abstract
Antibodies have long been shown to play a critical role in naturally acquired immunity to malaria, but it has been suggested that Plasmodium-specific antibodies in humans may not be long lived. The cellular mechanisms underlying B cell and antibody responses are difficult to study in human infections; therefore, we have investigated the kinetics, duration and characteristics of the Plasmodium-specific memory B cell response in an infection of P. chabaudi in mice. Memory B cells and plasma cells specific for the C-terminal region of Merozoite Surface Protein 1 were detectable for more than eight months following primary infection. Furthermore, a classical memory response comprised predominantly of the T-cell dependent isotypes IgG2c, IgG2b and IgG1 was elicited upon rechallenge with the homologous parasite, confirming the generation of functional memory B cells. Using cyclophosphamide treatment to discriminate between long-lived and short-lived plasma cells, we demonstrated long-lived cells secreting Plasmodium-specific IgG in both bone marrow and in spleens of infected mice. The presence of these long-lived cells was independent of the presence of chronic infection, as removal of parasites with anti-malarial drugs had no impact on their numbers. Thus, in this model of malaria, both functional Plasmodiumspecific memory B cells and long-lived plasma cells can be generated, suggesting that defects in generating these cell populations may not be the reason for generating short-lived antibody responses. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
13. Monoclonal antibodies that identify the CD3 molecules expressed specifically at the surface of porcineγδ-T cells.
- Author
-
Huaizhi Yang, Parkhouse, R. Michael E., and Wileman, Thomas
- Subjects
CD antigens ,CELL surface antigens ,MONOCLONAL antibodies ,IMMUNOGLOBULINS ,T cells ,CELL proliferation - Abstract
The CD3 antigen is a surface structure associated with the T-cell receptor (TCR) to form a complex involved in antigen recognition and signal transduction. Reports on the structures of the CD3 molecules associated withαβ- andγδ-TCR have been contradictory. To investigate this issue, we raised a panel of monoclonal antibodies (mAb) against purified porcine CD3 molecules. Unlike the conventional anti-CD3, these mAb reacted specifically with peripheralγδ-T cells, but not withαβ-T cells. Immunoprecipitation showed that the antibody recognized a subset of CD3 molecules that were associated withγδ-TCR. Also unlike the conventional anti-CD3, these mAb, though directed at two different epitope groups, failed to induce antigenic modulation, T-cell proliferation and CD3-redirected cytotoxicity. Taken together, these results suggest that there are differences in the antigenicity, signal transduction potentials and probably structural differences between the CD3 molecules expressed at the surface ofαβ- andγδ-T cells. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
14. Synergy between interleukin-2 and prothymosin α for the increased generation of cytotoxic T lymphocytes against autologous human carcinomas.
- Author
-
Voutsas, Ioannis F., Baxevanis, Constantin N., Gritzapis, Angelos D., Missitzis, Ioannis, Stathopoulos, George P., Archodakis, George, Banis, Constantin, Voelter, Wolfgang, and Papamichail, Michael
- Subjects
INTERLEUKIN-2 ,CANCER ,T cells ,ANTINEOPLASTIC antibiotics ,MONOCLONAL antibodies ,IMMUNOGLOBULINS ,CELL proliferation - Abstract
Peripheral blood mononuclear cells (PBMC) from cancer patients were cultured in vitro with irradiated autologous tumor cells isolated from malignant effusions (mixed lymphocyte tumor cultures, MLTC) and low-dose (50 IU/ml) recombinant interleukin-2 (IL-2). The combination of IL-2 and prothymosin α (ProTα) resulted in a greater PBMC-induced response to the autologous tumor than that brought about by IL-2 alone. In particular, ProTα specifically enhanced the CD4
+ T-cell-mediated proliferation against the autologous tumor. CD4+ T cells seemed to recognize tumor antigens presented by HLA-DR molecules expressed on the autologous monocytes, since preincubation of the latter with an anti-HLA-DR monoclonal antibody (mAb) abrogated the response. In addition, MLTC set up with IL-2 and ProTα also generated more MHC-class-I-restricted cytotoxic T lymphocytes (CTL) against the autologous tumor than did MLTC set up with IL-2 alone. The MLTC-induced CTL contained high levels of cytoplasmic perforin and their development was strictly dependent on the presence of both autologous CD4+ T cells and monocytes. In the absence of either population there was a strong impairment of both proliferative and cytotoxic responses which was not restored by the presence of ProTα. In contrast, when both cell populations were present, ProTα exerted optimal enhancement of CD4+ T cell proliferation, which was associated with potentiated CTL responses. Our data emphasize the role of ProTα for the enhancement of IL-2-induced CTL responses against autologous tumor cells. Such responses require collaborative interactions between CD4+ , CD8+ T cells and monocytes as antigen-presenting cells. Our data are relevant for adoptive immunotherapeutic settings utilizing IL-2 and ProTα-induced autologous-tumor-specific CTL. [ABSTRACT FROM AUTHOR]- Published
- 2000
- Full Text
- View/download PDF
15. Overcoming PD-1 Inhibitor Resistance with a Monoclonal Antibody to Secreted Frizzled-Related Protein 2 in Metastatic Osteosarcoma.
- Author
-
Nasarre, Patrick, Garcia, Denise I., Siegel, Julie B., Bonilla, Ingrid V., Mukherjee, Rupak, Hilliard, Eleanor, Chakraborty, Paramita, Nasarre, Cécile, Yustein, Jason T., Lang, Margaret, Jaffa, Aneese A., Mehrotra, Shikhar, and Klauber-DeMore, Nancy
- Subjects
SECRETED frizzled-related proteins ,PROGRAMMED cell death 1 receptors ,ENDOTHELIAL cells ,IMMUNOGLOBULINS ,OSTEOSARCOMA ,ANIMAL experimentation ,MONOCLONAL antibodies ,METASTASIS ,LUNG tumors ,APOPTOSIS ,LYMPHOCYTES ,COENZYMES ,CELL proliferation ,MEMBRANE proteins ,CELL lines ,T cells ,MICE ,IMMUNOTHERAPY - Abstract
Simple Summary: Osteosarcoma (OS) is the most common bone tumor in the pediatric population, and long-term survival occurs in less than a third of the population with metastatic or recurrent tumors. Secreted frizzled-related protein 2 (SFRP2) promotes metastatic OS cell migration and tumor angiogenesis. This study aimed to assess the role of antagonizing SFRP2 with a humanized monoclonal antibody to SFRP2 (hSFRP2 mAb) in OS metastases in vivo and the role of SFRP2 in T-cells. Our results demonstrate that hSFRP2 mAb treatment inhibits metastases in two metastatic models of OS and can overcome resistance to a PD-1 monoclonal antibody. hSFRP2 mAb treatment restores T-cell proliferation and, in T-cells, inhibits NFATc3, CD38 and PD-1 expression. We conclude that SFRP2-targeted immunotherapy reduces the growth of metastatic osteosarcoma, not only through a direct antitumor and antiangiogenic effect but also by impacting the immune system. Secreted frizzled-related protein 2 (SFRP2) promotes the migration/invasion of metastatic osteosarcoma (OS) cells and tube formation by endothelial cells. However, its function on T-cells is unknown. We hypothesized that blocking SFRP2 with a humanized monoclonal antibody (hSFRP2 mAb) can restore immunity by reducing CD38 and PD-1 levels, ultimately overcoming resistance to PD-1 inhibitors. Treating two metastatic murine OS cell lines in vivo, RF420 and RF577, with hSFRP2 mAb alone led to a significant reduction in the number of lung metastases, compared to IgG1 control treatment. While PD-1 mAb alone had minimal effect, hSFRP2 mAb combination with PD-1 mAb had an additive antimetastatic effect. This effect was accompanied by lower SFRP2 levels in serum, lower CD38 levels in tumor-infiltrating lymphocytes and T-cells, and lower PD-1 levels in T-cells. In vitro data confirmed that SFRP2 promotes NFATc3, CD38 and PD-1 expression in T-cells, while hSFRP2 mAb treatment counteracts these effects and increases NAD
+ levels. hSFRP2 mAb treatment further rescued the suppression of T-cell proliferation by tumor cells in a co-culture model. Finally, hSFRP2 mAb induced apoptosis in RF420 and RF577 OS cells but not in T-cells. Thus, hSFRP2 mAb therapy could potentially overcome PD-1 inhibitor resistance in metastatic osteosarcoma. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
16. Mechanism of T cell-derived helper factor production upon stimulation with pokeweed mitogen in humans.
- Author
-
Suzuki, N. and Sakane, T.
- Subjects
T cells ,B cells ,CELL proliferation ,CELL differentiation ,IMMUNOGLOBULINS ,MITOGENS ,CELL communication - Abstract
T cell-derived helper factors can cause activated B cells to proliferate and differentiate into immunoglobulin (Ig)-secreting cells. In the pokeweed mitogen (PWM)-driven Ig production system, the cell-cell interaction necessary for the production of the helper factors was analysed. T cells were pulsed with PWM with or without autologous monocytes. The T cells were then isolated, and incubated for 48 h. Supernatants were tested for their ability to promote differentiation of activated B cells. We found that cell-cell contact between T cells and monocytes for the first 3 h of culture is required to produce the T cell-derived helper factors upon stimulation with PWM. We next examined which T cell subsets are involved in the production of helper factors and which surface molecules either on T cells or on monocytes are responsible for the cell-cell interaction to produce helper factors. A series of monoclonal antibodies were added to T cell subsets with monocytes during the PWM-pulsed period. Although T4
+ and T8+ cells could produce almost equal amounts of helper factor activity upon PWM-stimulation, the interactions between T3 and T4 antigens on T4+ cells and Ia-like antigens on monocytes and those between T3 and T8 antigens on T8+ cells and HLA class I antigens on monocytes are respectively essential for the production of T4+ cell-derived and T8+ cell derived helper factors. [ABSTRACT FROM AUTHOR]- Published
- 1988
17. IL-2 normalizes defective suppressor T cell function of patients with systemic lupus erythematosus in vitro.
- Author
-
Volk, H. D. and Diamantstein, T.
- Subjects
LYMPHOCYTES ,T cells ,SYSTEMIC lupus erythematosus ,HLA histocompatibility antigens ,CELL proliferation ,IMMUNOGLOBULINS ,ANTINEOPLASTIC agents - Abstract
During autologous mixed lymphocyte reaction (AMLR) both helper and suppressor T cells capable of regulating B cell responses are generated. The proliferative response of T cells as well as the generation of T suppressor cells in the AMLR of patients with active systemic lupus erythematosus (SLE) is diminished. In contrast, the T helper cells generated in the AMLR show a hyperactivity. The diminished HLA-class II antigen expression observed on non-T cells of SLE origin was restored by treatment of the cells with gamma-interferon (γ-IFN). When tested by immunoglobulin secretion, γ-IFN enhanced T helper cell activity but failed to affect T cell proliferation and T suppressor cell generation in the AMLR derived from patients with SLE. Human recombinant interleukin 2 restores both the proliferative response of T cells and the induction of T suppressor cells in AMLR. [ABSTRACT FROM AUTHOR]
- Published
- 1986
18. Impairment of T cell activation in burn patients: a possible mechanism of thermal injury--induced immunosuppression.
- Author
-
Teodorczyk-Injeyan, Julita A., Sparkes, B. G., Mills, G. B., Petfrs, W. J., and Falk, R. E.
- Subjects
T cells ,CELL proliferation ,LYMPHOCYTES ,IMMUNOGLOBULINS ,ANTIGENS ,IMMUNOSUPPRESSION - Abstract
In the burn patient, the mechanisms leading to impaired T lymphocyte activity are unclear. The capacity for T cell proliferation and the expression of Tac antigen (IL-2 receptor) was assessed during the post-burn period in patients with injuries ranging from 5-68%, total body surface area. T cell-dependent (polyclonal) immunoglobulin synthesis, mixed lymphocyte reaction and Interleukin-2 production were also determined in these patients and correlated with survival. Surviving patients demonstrated a transient reduction while terminal patients exhibited a permanent reduction in the number of Tac lymphocytes, unrelated to the absolute number of T cells, during the post-burn period. The reduced percentage of lL-2 receptor-expressing T cells coincided with the suppressed antibody response and reduced alloreactivity. Although the concentration of IL -2 was decreased in all patients throughout the hospitalization period, surviving patients showed a gradual increase in its production while terminal patients gradually decreased to undetectable levels. Exogenous recombinant IL-2 induced a significant enhancement of in-vitro polyclonal immunoglobulin production and blastogenesis in the mixed lymphocyte reaction in immunosuppressed patients who demonstrated up to 50%, reduction in the percentage of IL-2 receptor positive cells. Thus, the reduced capacity for production of and response to lL-2 alter thermal injury may lead to the immunosuppression due to a lack of T lymphocyte clonal expansion. The permanent nature of this detect in patients who died from fatal sepsis may suggest a causative relationship. [ABSTRACT FROM AUTHOR]
- Published
- 1986
19. Treatment of a low grade T cell proliferation with monoclonal antibody.
- Author
-
Chandra, R. K.
- Subjects
T cells ,CELL proliferation ,MONOCLONAL antibodies ,IMMUNOGLOBULINS ,CETUXIMAB ,INFLIXIMAB - Abstract
A therapeutic trial of a pan-T monoclonal antibody is described in a patient with a low grade mature T cell proliferation and haemopoietic suppression. The study shows that non-complement fixing IgGl antibodies can be highly effective opsonins, and the dose required can be estimated from in vitro studies. It is demonstrated that therapeutic failure occurred due to the appearance of anti-mouse antibodies and not to anligenic modulation or reticuloendothelial blockade. The literature is reviewed and the potential role of serotherapy in malignant disorders is discussed. [ABSTRACT FROM AUTHOR]
- Published
- 1983
20. The T-cell response to haptenated insulins I. THE PROLIFERATIVE RESPONSE.
- Author
-
Wallace, C.Ft., Briffa, J., Mccafferty, I., Askenase, P.W., and Chain, B.M.
- Subjects
T cells ,INSULIN ,CELL proliferation ,LYMPH nodes ,MAJOR histocompatibility complex ,IMMUNOGLOBULINS - Abstract
Mice were primed with TNP-derivatized insulin, or TNP-Mycobacteria, and lymph node cells were challenged in vitro with haptenated and unhaptenated antigens. Using either priming antigen, T-cell proliferative responses could be obtained to TNP-insulin. In B10 (H-2
b ), mice, which are responders to beef insulin (BI), but not to pork insulin (PI), TNP-BI or TNP-PI primed a response to TNP beef and TNP pork insulins, and to beef but not pork insulin, suggesting that a proportion of the response was directed to the modified portion of the molecule. However, priming with BI resulted in responsiveness to TNP-PI, but not to PI. Also, TNP-BI stimulated an augmented proliferative response in BI-primed mice. These results suggest that TNP modification can alter the antigenicity of the carrier molecule, perhaps by enhancing weak interactions with MHC molecules on presenting cells. Finally, there was no evidence that the TNP-dependent response to TNP-pork insulin was down-regulated by suppressor cells directed at the carrier molecule. [ABSTRACT FROM AUTHOR]- Published
- 1989
21. The rat T-cell differentiation marker RT6.1 is more polymorphic than its alloantigenic counterpart RT6.2.
- Author
-
Koch, F., Kashan, A., and Thiele, H.-G.
- Subjects
IMMUNOGLOBULINS ,T cells ,CELL proliferation ,BIOMARKERS ,ANTIGENS ,RATS - Abstract
Utilizing allotype-specific antibodies to immunoprecipitate RT6.2 from DA.68 rat lymphocyte lysates, we have shown this antigen recently to be composed of two related, non-glycosylated polypeptides with apparent molecular weights (MW) of 24,000 and 26,000 (reducing conditions), which evidently are anchored in the cell membrane by covalent linkage to phosphatidylinositol. The present report shows that RT6. 1 allotype-specific antibodies precipitate a more complex pattern of bands from LEW.6A rat lymphocyte lysates. These consist of an endo-F-resistant RT6.2-like 25/ 27,000 MW doublet (reducing conditions) as well as at least five additional endo-F-sensitive, endo-H- resistant polypeptides of 30,000, 32,000, 33,000, 34,000, 35,000 MW. Endo-F treatment seems to convert the additional higher to the lower molecular weight forms. In contrast to the endo-F-resistant 25/27,000 MW doublet, the higher MW forms of RT6. 1 partly bind to lentil lectin and concanavalin A (Con A). Two-dimensional electrophoretic analyses (NEPHGE/SDS-PAGE) reveal similar patterns of charge heterogeneity of the lower and higher MW forms of RT6. 1. Neuraminidase treatment does not affect the pIs of the lower MW forms but shifts the pIs of the higher MW forms to those of the lower ones. All forms of RT6. 1 evidently employ the covalent linkage to phosphatidylinositol for membrane anchorage. Identical patterns of molecular forms-the doublet for RT6.2, the polymorphic pattern for RT6. 1-are observed upon immunoprecipitation of the alloantigens from the lysates of corresponding series of inbred strains of rats with both allotype-specific antibodies and a polyclonal rabbit serum recognizing a common determinant on both alloantigens. [ABSTRACT FROM AUTHOR]
- Published
- 1988
22. Heterogeneity in the activation requirements of T cells stimulated by phytohaemagglutinin.
- Author
-
Warren, H. S. and Bezos, A.
- Subjects
T cells ,CELL proliferation ,MONOCLONAL antibodies ,IMMUNOGLOBULINS ,MOLECULAR cloning ,CELL populations - Abstract
Data are presented showing that resting T cells proliferated in response to phytohaemagglutinin (PHA) provided that either sheep erythrocytes (SRC) or interleukin-2 (IL-2) was added. Proliferation requiring PHA and SRC was inhibited by anti-CD2 monoclonal antibody (OKT11) and anti-CD3 monoclonal antibody (OKT3). These monoclonal antibodies only partially inhibited IL-2 production stimulated by PHA and SRC, and added IL-2 did not restore proliferation in these cultures. Low concentrations of cyclosporine inhibited both proliferation and IL-2 production (ED
50 =12 and 9 ng/ml, respectively) and this inhibition was partially relieved in the presence of added IL-2 (ED50 = 110 ng/ml). In contrast, proliferation stimulated by PHA with exogenous IL-2 was not inhibited in the presence of OKT11, and moderate concentrations of cyclosporine were required to inhibit proliferation (ED50 = 49 ng/ml). Evidence was obtained, from analysis of cultures at limiting dilution, to suggest that the different requirements for stimulation of PHA-responsive T cells reflected different T-cell subpopulations. The majority of PHA-responsive cells proliferated in the presence of PHA and SRC, whereas only a minority proliferated in the presence of PHA and exogenous IL-2. [ABSTRACT FROM AUTHOR]- Published
- 1987
23. Monoclonal antibodies against a rat leucocyte antigen block antigen-induced T-cell responses via an effect on accessory cells.
- Author
-
Arvieux, J., Jefferies, W. A., Paterson, D. J., Williams, A. F., and Green, J. R.
- Subjects
MONOCLONAL antibodies ,LEUCOCYTES ,CELL proliferation ,T cells ,IMMUNOGLOBULINS ,CYTOLOGY ,RATS - Abstract
The M RC OX-45 and OX-46 mouse monoclonal antibodies recognize a rat cell surface glycoprotein of 45,000 MW that is present on a wide variety of haematopoietic cells and on endothelial cells. MRC OX-45 IgG or F(ab')2 blocked the primary mixed lympocyte response (MLR) and the secondary response of T lymphocytes to the soluble antigen DNP-BGG. In contrast, the antibodies had no effect on the cytotoxic activity of specific (CTL) or non-specific (NK) killer cells or on proliferative responses stimulated by lectins or oxidative mitogenesis. The inhibitory effect was at the level of stimulator cells rather than responders since mouse anti-rat xenogeneic MLRs were inhibited but rat anti-mouse responses were unaffected. However, the effect was not a direct one because inhibition was seen when irradiated spleen cells were used as stimulators but not when cell populations highly enriched for dendritic cells were used. In the latter case, inhibition potentiated by antibody could be resto red if a peritoneal cell population enriched for macrophages was added back to the cultures. The inhibitory effects of these monoclonal antibodies seem most likely to be due to potentiation of non- specific suppression by macrophages. [ABSTRACT FROM AUTHOR]
- Published
- 1986
24. Characteristics of human B cells responsive to the T-independent mitogen <em>Branhamella catarrhalis</em>.
- Author
-
Calvert, Jane E. and Calogeras, Antonia
- Subjects
B cells ,MITOGENS ,T cells ,TONSILS ,IMMUNOGLOBULINS ,CELL proliferation - Abstract
Non-T cells from tonsil or blood were fractionated according to buoyant density, isotype of surface immunoglobulin, or the ability to form rosettes with mouse erythrocytes. Each fraction was tested for the ability to proliferate in response to B. catarrhalis (Bc) and, for comparison, Staphylococcus aureus Cowan 1 (SAC) or an MLR supernatant (TF). Cells in all density fractions responded to Bc, the greatest response occurring in the high-density cell fraction. SAC could similarly induce proliferation in high-density cells, in contrast to TF which preferentially activated cells in the low-density fraction. When cells were fractionated by rosetting with mouse erythrocytes, both fractions (MRBC-R
+ and MRBC-R- ) responded to Be and to SAC, whereas the greatest response to TF occurred in the MRBC-R- cell fraction. Depletion of sIgD+ sIgM+ cells almost completely abolished the response to Bc, suggesting that responsive cells express both these classes of immunoglobulin on their membrane. Furthermore inclusion of anti-δ antibodies in cultures resulted in failure to proliferate in response to Bc. These data strongly suggest that Bc, like SAC but in contrast to TF, is able to stimulate proliferation in cells with the characteristics of resting B cells, i.e. high-density, sIgD+ cells which form rosettes with MRBC. This may be related to the fact that Bc, like SAC, is able to bind to human immunoglobulins. [ABSTRACT FROM AUTHOR]- Published
- 1986
25. Presentation by peritoneal macrophages: modulation by antibody-antigen complexes.
- Author
-
Perkins, K. A. and Chain, B. M.
- Subjects
IMMUNOGLOBULINS ,MACROPHAGES ,IMMUNE complexes ,T cells ,LYMPHOKINES ,CELL proliferation - Abstract
The effects of immune complex formation on presentation was studied. Immune complexes between an IgG2a monoclonal anti-DNP antibody and TNP-KLH were produced, and the presentation of the carrier molecule by peritoneal macrophages to KLH-primed T cells was monitored. Complex formation was found to enhance the proliferative response of the T cells. This enhancement was specific, was not mediated by lymphokine release, and required antibody with an intact Fc portion. The significance of these results in terms of immune regulation and antigen presentation is discussed. [ABSTRACT FROM AUTHOR]
- Published
- 1986
26. Inhibition by Fab and Fab′2 monoclonal anti-Ia antibody fragments of T-lymphocyte proliferative responses.
- Author
-
Lemonnier, F., Dubreuil, P., and Caillol, Danielle
- Subjects
T cells ,MONOCLONAL antibodies ,FISSURELLIDAE ,CELL proliferation ,IMMUNOGLOBULINS ,IMMUNOLOGY - Abstract
We investigated the capacity of anti-Ia monoclonal antibody Fab and Fab′2 fragments to inhibit keyhole limpet haemocyanin (KLH) or concanavalin A (Con A)-induced T-cell proliferations. Both types of fragments of anti-l-Ak and anti-I-E/Ck monoclonal antibodies inhibited these responses. On a protein concentration basis, the inhibitory effects of fragmented antibodies were less pronounced than those of undigested molecules. However, once the differences in antigen-binding capacity were compensated, antibody fragments were as efficient inhibitors as undigested molecules. These results suggest (i) that masking of Ia antigenic determinants is the essential mechanism of anti-Ia antibody-mediated inhibitory effect; (ii) that some KLH-specific proliferating T lymphocytes are I-E/Ck restricted; (iii) that the Ia antigen role is not limited to restriction of cell interactions since the Con A-induced proliferation, a non-H-2 restricted response, is inhibited by anti-Ia Fab fragments. [ABSTRACT FROM AUTHOR]
- Published
- 1982
27. The inductive requirements for the primary <em>in vitro</em> generation of delayed-type hypersensitivity response to influenza virus in mice.
- Author
-
Leung, K. N., Mak, N. K., and Ada, G. L.
- Subjects
T cells ,ALLERGIES ,CELL division ,CELL proliferation ,CELL growth ,INFLUENZA viruses ,CELL-mediated lympholysis ,IMMUNOGLOBULINS - Abstract
Effector T cells (Td) which mediate delayed-type hypersensitivity reactions to influenza A virus can be generated in tissue culture using normal mouse spleen cells as the responder population. Addition of helper T cells enhances but is not essential for the production of Td cells. Both Ly 1 positive, I region restricted and Ly 2,3 positive, K,D region restricted effector cells are generated. Treating the responder cell population with anti-Ly I or anti-Ly 2,3 antibodies and complement prevented the generation of both classes of effector T cell, suggesting that the precursor Td cells are Ly 1,2,3 positive. Effector cells which are specific for the homologous virus or cross-reactive within the A strains of influenza virus are produced, as has been found previously in in vivo experiments. Depleting the cell population of phagocytic and plastic adherent cells resulted in a failure to produce Td cells, which showed a requirement for macrophage-like cells as accessory cells in the primary in vitro generation of Td cells. A variety of cells, such as peritoneal exudate cells, mitogen stimulated blasts or L929 fibroblast cells could serve as stimulator cells. Only Ly 2,3 positive, K,D region-restricted Td cells were produced when L929 cells were used as they lack I region-coded surface antigens. The 1 region-restricted DTH response was mapped to the IA sub-region of the H-2 gene complex. [ABSTRACT FROM AUTHOR]
- Published
- 1981
28. Induction of T-cell hyporesponsiveness by intrahepatic modulation of donor antigen-presenting cells.
- Author
-
Chung, S. W., Gorczynski, R. M., Dziadkowiec, I., and Levy, G. A.
- Subjects
T cells ,LYMPHOCYTES ,ANTIGENS ,IMMUNITY ,IMMUNOGLOBULINS ,CELL proliferation - Abstract
In this study, we examined the ability of varying populations of donor cells from B6 mice to induce hyporesponsiveness in T lymphocytes from C3H mice in vitro and in vivo. Small, resting B lymphocytes were inefficient stimulators of T-lymphocyte proliferation compared to splenic mononuclear cells (SMNC) and lipopolysaccharide (LPS)-induced B-cell blasts in vitro (P < 0.05). Pretreatment of SMNC with anti-B7-1 or anti-intracellular adhesion molecule-1 (ICAM-1) monoclonal antibodies (mAb) similarly resulted in inefficient stimulation of T-cell proliferation in vitro (P < 0.05). However, in vivo, only intrahepatic, but not intravenous, injection of donor cells into C3H mice resulted in decreased T-lymphocyte proliferation in response to restimulation by alloantigen. This effect was most pronounced following intrahepatic injection of resting B lymphocytes or SMNC pretreated with anti-ICAM-1 mAb compared to uninjected or intravenously injected mice (P < 0.05). The hyporesponsiveness was associated with an increased production of interleukin-4 (IL-4) by the responder T lymphocytes and correlated with enhanced skin allograft survival. These data demonstrate that intrahepatic injection of donor-derived cells induces T-lymphocyte hyporesponsiveness. The mechanism appears to be modulated by an ICAM-1-mediated signal resulting in expansion of an IL-4-producing T-lymphocyte population. [ABSTRACT FROM AUTHOR]
- Published
- 1995
29. IL-10 and IL-3 synergize to cause proliferation of human T cells.
- Author
-
Cohen, S.B.A.
- Subjects
INTERLEUKINS ,HEMATOPOIETIC stem cells ,CELL proliferation ,T cells ,CYTOKINES ,IMMUNOGLOBULINS - Abstract
nterleukin-3 (IL-3) is a well-documented haemopoietic growth factor, but its effects on T-cell function are less clear. Although this cytokine is a potent growth factor for CD4
- CD8- αβ T-cell receptor-expressing cells, it has few known effects on single-positive T cells. In this report it is shown that IL-3 synergizes with IL-10 to induced proliferation of T-cell lines and single-positive clones. Specificity was verified using blocking anti-IL-10 and anti-IL-3 neutralizing antibodies. This induction of proliferation was dose dependent. Taken together the results imply that IL-3 can act as a growth factor for T-cell lines and single-positive T-helper type-1 (Th1) CD4+ clones in the presence of a cofactor, IL-10, a cytokine that has been documented as being predominantly a Tcell inhibitory, and not proinflammatory, cytokine. [ABSTRACT FROM AUTHOR]- Published
- 1995
30. 1,25(OH)2D3 regulates c-myc mRNA levels in tonsillar T lymphocytes.
- Author
-
Karmali, R., Hewison, M., Rayment, N., Farrow, S. M., Brennan, A., Katz, D. R., and O'Riordan, J. L. H.
- Subjects
MESSENGER RNA ,CELL proliferation ,CELL receptors ,T cells ,PHYTOHEMAGGLUTININS ,IMMUNOGLOBULINS - Abstract
The effects of 1,25(OH)
2 D3 on proliferation, c-myc mRNA levels and 1,25(OH)2 D3 receptor expression in activated tonsillar T lymphocytes were studied. Activation of resting T cells with phytohaemagglutinin (PHA) for 72 hr led to an increase in proliferation, c-myc mRNA levels and to induction of 1,25(OH)2 D3 receptor expression. However, when activation was carried out in the presence of 1,25(OH)2 D3 , there was inhibition of PHA-stimulated proliferation and c-myc mRNA levels. Increased cell proliferation, c-myc mRNA expression and 1,25(OH)2 D3 receptor number were also observed, albeit to a lesser extent, when T cells were stimulated by phorbol myristate acetate (PMA), anti-CD3 antibody or A23187. However, in these eases 1,25(OH)2 D3 was unable to prevent increased proliferation or c-myc mRNA expression. PMA and anti-CD3 used in combination produced similar or greater changes in proliferation, c-myc mRNA levels, 1,25(OH)2 D3 receptor expression and responsiveness to the hormone when compared to PHA alone. Thus the inhibition of c-myc expression in activated T lymphocytes by 1,25(OH)2 D3 can be related to its anti-proliferative effects. Moreover this inhibition seems to be dependent on the level of 1,25(OH)2 D3 receptor expression, which in turn appears to be related to the degree of cell activation. [ABSTRACT FROM AUTHOR]- Published
- 1991
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.