ABSTRACT
Multiple myeloma (MM), considered an incurable hematological malignancy, is characterized by its clonal evolution of malignant plasma cells. Although the application of autologous stem cell transplantation (ASCT) and the introduction of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) have doubled the median overall survival to eight years, relapsed and refractory diseases are still frequent events in the course of MM. To achieve a durable and deep remission, immunotherapy modalities have been developed for relapsed/refractory multiple myeloma (RRMM). Among these approaches, chimeric antigen receptor (CAR) T-cell therapy is the most promising star, based on the results of previous success in B-cell neoplasms. In this immunotherapy, autologous T cells are engineered to express an artificial receptor which targets a tumor-associated antigen and initiates the T-cell killing procedure. Tisagenlecleucel and Axicabtagene, targeting the CD19 antigen, are the two pacesetters of CAR T-cell products. They were approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). Their development enabled unparalleled efficacy in combating hematopoietic neoplasms. In this review article, we summarize six promising candidate antigens in MM that can be targeted by CARs and discuss some noteworthy studies of the safety profile of current CAR T-cell therapy.
Subject(s)
Humans , ADP-ribosyl Cyclase 1/immunology , B-Cell Maturation Antigen/immunology , Immunotherapy, Adoptive/methods , Multiple Myeloma/therapy , Receptors, Chimeric Antigen/immunology , Receptors, G-Protein-Coupled/immunology , Signaling Lymphocytic Activation Molecule Family/immunology , Syndecan-1/immunology , T-Lymphocytes/immunologyABSTRACT
Objective: To explore the expression of SLAMF6 on CD8(+) T cells in patients with severe aplastic anemia (SAA) and its correlation with disease immune status. Methods: By flow cytometry (FCM), SLAMF6 expression level in peripheral blood CD8(+) T cells was detected in 21 patients with SAA and 15 normal controls respectively from February 2017 to April 2018. The correlation between SLAMF6 expression level and hematopoietic functions, including HGB, PLT, the neutrophil granulocyte and reticulocyte absolute value in peripheral blood, hyperplasia degree (percentage of granulocytes, erythrocytes, lymphocytes and megakaryocytes in bone marrow) and perforin, granzyme B, IFN-γ expression level in CD8(+) T cells were evaluated. To further confirm the effect of SLAMF6 on CD8(+) T cells, anti-SLAMF6 Ab was used to block SLAMF6 pathway (IgG as control), and FCM was used to detect the perforin, granzyme B, and IFN-γ production of CD8(+) T cells. Results: The expression of SLAMF6 on CD8(+) T cells in untreated SAA patients[(56.29±12.97)%]was significantly lower than that of normal controls[(80.96±7.36)%](t=-7.672, P<0.001). The expression of SLAMF6 on CD8(+) T cells in SAA patients were positively correlated with the HGB, PLT, the neutrophil granulocyte and reticulocyte absolute value in peripheral blood, percentage of granulocytes, erythrocytes in bone marrow (all P<0.05), but they were negatively correlated with the percentage of lymphocytes in bone marrow, and the expression of perforin, granzyme B, and IFN-γ of CD8(+) T cells (all P<0.05). After blocking SLAMF6 pathway by anti-SLAMF6 Ab, the expression levels of perforin, granzyme B and IFN-γ in SAA patients were significantly higher than those in the untreated group, and the differences were statistically significant (all P<0.05). Conclusions: SLAMF6 is significantly down-regulated on CD8(+) T cells in SAA patients, which may act as a negative immunoregulatory molecule participating in the mechanism of SAA by affecting the functional molecules secretion on CD8(+) T cells.
Subject(s)
Humans , Anemia, Aplastic , Bone Marrow , CD8-Positive T-Lymphocytes , Flow Cytometry , Perforin , Signaling Lymphocytic Activation Molecule FamilyABSTRACT
Introduction: Signaling lymphocyte activation molecule (SLAM) is a self-ligand receptor on the surface of activated T- and B-lymphocytes, macrophages, and DC. Studies have shown PBMC from healthy individuals exposed to Leishmania differ in IFN-γ production. Objective: We investigated the role of SLAM signaling pathway in PMBC from high (HP) and low (LP) IFN-γ producers exposed to L. braziliensis in vitro. Methods: PBMC from 43 healthy individuals were cultured with or without antigen, α-SLAM, rIL-12 and rIFN-γ. The cytokines production was evaluated by ELISA, and SLAM expression by flow cytometry. Results: L. braziliensis associated with rIFN-γ or rIL-12 reduced early SLAM but did not modify this response later in HP. α-SLAM did not alter CD3+SLAM+ expression, and not affected IFN-γ and IL-13 production, in both groups, but increased significantly IL-10 in HP. Leishmania associated with α-SLAM and rIL-12 increased IFN-γ in LP, as well as IL-13 in HP. LP group presented low IFN-γ and IL-13 production, and low SLAM expression. Conclusion: Collectively, these findings suggest that when PBMC from healthy individuals are sensitized with L. braziliensis in vitro, SLAM acts in modulating Th1 response in HP individuals and induces a condition of immunosuppression in LP individuals. (AU)
Introdução: A molécula de sinalização para ativação linfocítica (SLAM) é um receptor autoligante na superfície de linfócitos T e B ativados, macrófagos e DC. Estudos têm mostrado que PBMC de indivíduos saudáveis expostos à Leishmania diferem na produção de IFN-γ. Objetivo: Nós investigamos o papel da via de sinalização de SLAM em PMBC de altos produtores de IFN-γ (AP) e baixos (BP) expostos à L. braziliensis in vitro. Métodos: PBMC de 43 indivíduos saudáveis foram cultivadas com ou sem antígeno, α-SLAM, rIL-12 e rIFN-γ. Foi avaliada a produção de citocinas por ELISA e expressão de SLAM por citometria de fluxo. Resultados: L. braziliensis associado a rIFN-γ ou rIL-12 reduziu a expressão inicial de SLAM, mas não modificou esta resposta mais tarde em AP. α-SLAM não alterou a expressão de CD3+SLAM+, e não afetou a produção de IFN-γ e IL-13, em ambos os grupos, mas aumentou significativamente IL-10 em AP. Leishmania associada a α-SLAM e rIL-12 aumentou IFN-γ em BP, assim como IL-13 em AP. BP apresentaram baixa produção de IFN-γ e IL-13 e baixa expressão de SLAM. Conclusão: Coletivamente, esses achados sugerem que quando PBMC de indivíduos saudáveis são sensibilizados por L. braziliensis in vitro, SLAM atua na modulação da resposta Th1 em indivíduos AP e induz uma condição de imunossupressão em indivíduos BP. (AU)
Subject(s)
Leishmania braziliensis , Cytokines , Immunosuppression Therapy , Signaling Lymphocytic Activation Molecule FamilyABSTRACT
Introduction: Common variable immunodeficiency (CVID) is an immunological disorder characterized by defective antibody production. Objectives: To study lymphocytes number, surface activation molecules, cell markers, lymphoproliferative response, cytokine production, and cell death. Methods: A study was led on thirty four patients with CVID selected from the Division of Clinical Immunology and Allergies of the Faculty of Medicine of São Paulo University (FMUSP), Brazil. Peripheral mononuclear blood cells (PBMC) of CVID patients and healthy individuals were evaluated in regard to the expression of cell surface markers, activation molecules, lymphoproliferative response, cytokine synthesis and apoptosis. Results: CVID patients showed decrease in T and B lymphocyte counts, CD25, CD69, CD40L, and CD70 expression, and low synthesis levels of IL-4 and IL-5. Furthermore, their lymphocytes were more susceptible to apoptosis following activation. Conclusion: The higher susceptibility to apoptosis following activation may also be responsible for the decrease in the expression of activation molecules and CD40L, in cytokine synthesis, and in levels of circulating T and B cells.
Introdução: A imunodeficiência comum variável (CVID) é uma enfermidade imune caracterizada pela produção deficiente de anticorpos. Objetivo: Avaliar o número de linfócitos, moléculas de ativação, resposta linfoproliferativa, produção de citocinas e morte celular. Métodos: Foram selecionados 34 pacientes com CVID na Divisão de Imunologia Clínica e Alergia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), Brasil. Células mononucleares obtidas a partir de sangue periférico (PBMC) foram isoladas para avaliação de marcadores de superfície celular, moléculas de ativação, resposta linfoproliferativa, quantificação de citocinas e apoptose. Resultados: Os pacientes analisados apresentaram diminuição na contagem de linfócitos T e B, expressão de CD25, CD69, CD40L, CD70, e baixa produção de IL-4 e IL-5. Os linfócitos se apresentaram mais suscetíveis à apoptose pós-ativação. Conclusão: A maior susceptibilidade à apoptose pós-ativação pode ser responsável pela diminuição na expressão de moléculas de ativação e CD40L, síntese de citocinas e linfócitos T e B circulantes.
Subject(s)
Humans , Common Variable Immunodeficiency/blood , Apoptosis , Antibodies/blood , B-Lymphocytes , T-Lymphocytes , Case-Control Studies , Cytokines , Cell Death , Signaling Lymphocytic Activation Molecule FamilyABSTRACT
<p><b>BACKGROUND</b>The SLAM family recently has been reported to show an important biological role in lymphocyte development and immunological function, and it is efficient to highly purify hematopoietic stem cells using a simple combination of SLAM family members. To elucidate the presence of this family on acute lymphoblastic leukemia (ALL), as well as its relationship with the leukemia-initiating potential, we analyzed the expression pattern of this family members on human ALL progenitor cells, combined with serial xenotransplantation assay.</p><p><b>METHODS</b>Expression analysis was carried out by flow cytometry. We combined the expression pattern of human CD(150), CD(244) and CD(48) with serial xenotransplantation of B-ALL progenitor cells to indicate their relationship.</p><p><b>RESULTS</b>CD(48) and CD(244) were expressed on most B-ALL progenitor cells, the percentage being (93.08 ± 6.46)% and (63.37 ± 29.31)%, respectively. Interestingly, the proportion of CD(150)(+) cells declined obviously in engrafted cases ((24.94 ± 7.32)%) compared with non-engrafted cases ((77.54 ± 5.93)%, P < 0.01), which indicated that only blast cells with low percentage of CD(150)(+) population were able to reconstitute leukemia into primary, secondary and tertiary NOD/SCID mice.</p><p><b>CONCLUSIONS</b>SLAM family members are present on B-ALL progenitor cells and the leukemia-initiating potential of leukemic blasts is correlated negatively with the proportion of CD(150)(+) cells, the percentage of which can serve as a useful predictor for engraftment success of B-ALL to immune deficient mice.</p>