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Molecular Immunology in Hematological Disorders
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Molecular Immunology in Hematological Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 23323

Special Issue Editor

Prof. Dr. Akiyoshi Takami

E-Mail Website
Guest Editor
Department of Medicine, Division of Hematology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan
Interests: immunotherapy for hematological cancers; hematopoietic stem cell transplantation; laboratory hematology; the immunological effects of phytochemicals; transfusion medicine; bone marrow failure
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The mechanism by which hematological malignancies such as leukemia, lymphoma, and myeloma develop and proliferate in vivo is not yet fully understood. However, the possibility of eradicating cancer cells not only through allogeneic hematopoietic stem cell transplantation but also single-molecule targeted therapy, such as with CAR-T cells, suggests that the immune system, including innate and adaptive immunity, plays an important role in the development and pathophysiology of hematological malignancies. The involvement of immunological mechanisms has also been suggested in benign hematological disorders such as acquired aplastic anemia, paroxysmal nocturnal hemochromatosis, immune thrombocytopenia, thrombotic microangiopathy, and hemolytic anemia. In addition, hematological abnormalities associated with immunological dysregulation have also been noted in infectious diseases such as COVID-19 and autoimmune diseases. Therefore, there is a close pathophysiological relationship between hematological disorders and the immune system, and elucidation of these molecular mechanisms will advance the diagnosis and treatment of benign and malignant hematologic diseases, infectious diseases, and autoimmune diseases. This Special Issue focuses on molecular immunology in hematology and specifically welcomes studies that elucidate molecular immunological mechanisms in the diagnosis and treatment of hematological disorders, in addition to other topics that are relevant to the Special Issue theme.

Prof. Dr. Akiyoshi Takami
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Anemia
  • Bioinformatics
  • COVID-19
  • Functional genetics
  • Genetically-engineered therapy
  • Hematopoietic stem cell transplantation
  • Leukemia
  • lymphoma
  • Myeloma
  • Thrombocytopenia

Published Papers (7 papers)

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Editorial

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3 pages, 179 KiB  
Editorial
Molecular Immunology in Hematological Disorders
by Akiyoshi Takami
Int. J. Mol. Sci. 2022, 23(17), 9584; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179584 - 24 Aug 2022
Viewed by 1131
Abstract
This Special Issue aims to highlight the molecular mechanisms involved in the development and progression of hematologic malignancies such as leukemia, lymphoma, and myeloma [...] Full article
(This article belongs to the Special Issue Molecular Immunology in Hematological Disorders)

Research

Jump to: Editorial, Review, Other

12 pages, 2559 KiB  
Article
Synergistic Effects of Venetoclax and Daratumumab on Antibody-Dependent Cell-Mediated Natural Killer Cytotoxicity in Multiple Myeloma
by Ayano Nakamura, Susumu Suzuki, Jo Kanasugi, Masayuki Ejiri, Ichiro Hanamura, Ryuzo Ueda, Masao Seto and Akiyoshi Takami
Int. J. Mol. Sci. 2021, 22(19), 10761; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910761 - 05 Oct 2021
Cited by 7 | Viewed by 4730
Abstract
The prognosis of multiple myeloma (MM) has drastically improved owing to the development of new drugs, such as proteasome inhibitors and immunomodulatory drugs. Nevertheless, MM is an extremely challenging disease, and many patients are still refractory to the existing therapies, thus requiring new [...] Read more.
The prognosis of multiple myeloma (MM) has drastically improved owing to the development of new drugs, such as proteasome inhibitors and immunomodulatory drugs. Nevertheless, MM is an extremely challenging disease, and many patients are still refractory to the existing therapies, thus requiring new treatment alternatives. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 that shows efficacy in MM not only as a single agent but also in combination therapy, especially for MM patients with translocation t(11;14). However, many patients are refractory to this drug. Here, we treated the MM cell lines KMS12PE and KMS27 with a combination treatment of venetoclax targeting BCL-2 and daratumumab targeting CD38 to evaluate the synergistic cytotoxicity of these drugs in vitro. MM cell lines were co-cultured with natural killer (NK) cells at an effector:target ratio of 0.3:1 in the presence of serial concentrations of daratumumab and venetoclax, and the resulting apoptotic MM cells were detected by flow cytometry using annexin V. These results indicated that the antibody-dependent cell-mediated NK cytotoxicity was enhanced in KMS12PE and KMS27 cells harboring t(11;14) with a high BCL-2 expression, suggesting that the combination treatment of venetoclax and daratumumab should be especially effective in patients with these characteristics. Full article
(This article belongs to the Special Issue Molecular Immunology in Hematological Disorders)
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Review

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19 pages, 752 KiB  
Review
The Role of T Cell Immunity in Monoclonal Gammopathy and Multiple Myeloma: From Immunopathogenesis to Novel Therapeutic Approaches
by Ivana Lagreca, Giovanni Riva, Vincenzo Nasillo, Patrizia Barozzi, Ilaria Castelli, Sabrina Basso, Francesca Bettelli, Davide Giusti, Angela Cuoghi, Paola Bresciani, Andrea Messerotti, Andrea Gilioli, Valeria Pioli, Corrado Colasante, Daniela Vallerini, Ambra Paolini, Monica Maccaferri, Francesca Donatelli, Fabio Forghieri, Monica Morselli, Elisabetta Colaci, Giovanna Leonardi, Roberto Marasca, Leonardo Potenza, Rossella Manfredini, Enrico Tagliafico, Tommaso Trenti, Patrizia Comoli and Mario Luppiadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(9), 5242; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095242 - 08 May 2022
Cited by 7 | Viewed by 3097
Abstract
Multiple Myeloma (MM) is a malignant growth of clonal plasma cells, typically arising from asymptomatic precursor conditions, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Profound immunological dysfunctions and cytokine deregulation are known to characterize the evolution of the disease, [...] Read more.
Multiple Myeloma (MM) is a malignant growth of clonal plasma cells, typically arising from asymptomatic precursor conditions, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Profound immunological dysfunctions and cytokine deregulation are known to characterize the evolution of the disease, allowing immune escape and proliferation of neoplastic plasma cells. In the past decades, several studies have shown that the immune system can recognize MGUS and MM clonal cells, suggesting that anti-myeloma T cell immunity could be harnessed for therapeutic purposes. In line with this notion, chimeric antigen receptor T cell (CAR-T) therapy is emerging as a novel treatment in MM, especially in the relapsed/refractory disease setting. In this review, we focus on the pivotal contribution of T cell impairment in the immunopathogenesis of plasma cell dyscrasias and, in particular, in the disease progression from MGUS to SMM and MM, highlighting the potentials of T cell-based immunotherapeutic approaches in these settings. Full article
(This article belongs to the Special Issue Molecular Immunology in Hematological Disorders)
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26 pages, 1604 KiB  
Review
Coagulopathy and Fibrinolytic Pathophysiology in COVID-19 and SARS-CoV-2 Vaccination
by Shinya Yamada and Hidesaku Asakura
Int. J. Mol. Sci. 2022, 23(6), 3338; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063338 - 19 Mar 2022
Cited by 11 | Viewed by 5114
Abstract
Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is frequently complicated by thrombosis. In some cases of severe COVID-19, fibrinolysis may be markedly enhanced within a few days, resulting in fatal bleeding. In the treatment of [...] Read more.
Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is frequently complicated by thrombosis. In some cases of severe COVID-19, fibrinolysis may be markedly enhanced within a few days, resulting in fatal bleeding. In the treatment of COVID-19, attention should be paid to both coagulation activation and fibrinolytic activation. Various thromboses are known to occur after vaccination with SARS-CoV-2 vaccines. Vaccine-induced immune thrombotic thrombocytopenia (VITT) can occur after adenovirus-vectored vaccination, and is characterized by the detection of anti-platelet factor 4 antibodies by enzyme-linked immunosorbent assay and thrombosis in unusual locations such as cerebral venous sinuses and visceral veins. Treatment comprises high-dose immunoglobulin, argatroban, and fondaparinux. Some VITT cases show marked decreases in fibrinogen and platelets and marked increases in D-dimer, suggesting the presence of enhanced-fibrinolytic-type disseminated intravascular coagulation with a high risk of bleeding. In the treatment of VITT, evaluation of both coagulation activation and fibrinolytic activation is important, adjusting treatments accordingly to improve outcomes. Full article
(This article belongs to the Special Issue Molecular Immunology in Hematological Disorders)
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13 pages, 884 KiB  
Review
The Impact of NLRP3 Activation on Hematopoietic Stem Cell Transplantation
by J. Luis Espinoza, Kosuke Kamio, Vu Quang Lam and Akiyoshi Takami
Int. J. Mol. Sci. 2021, 22(21), 11845; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111845 - 31 Oct 2021
Cited by 5 | Viewed by 2214
Abstract
NLR family pyrin domain-containing 3 (NLRP3) is an intracellular protein that after recognizing a broad spectrum of stressors, such as microbial motifs and endogenous danger signals, promotes the activation and release of the pro-inflammatory cytokines IL-1β and IL-18, thus playing an essential role [...] Read more.
NLR family pyrin domain-containing 3 (NLRP3) is an intracellular protein that after recognizing a broad spectrum of stressors, such as microbial motifs and endogenous danger signals, promotes the activation and release of the pro-inflammatory cytokines IL-1β and IL-18, thus playing an essential role in the innate immune response. Several blood cell types, including macrophages, dendritic cells, and hematopoietic stem and progenitor cells (HSPCs), express NLRP3, where it has been implicated in various physiological and pathological processes. For example, NLRP3 participates in the development and expansion of HSPCs, and their release from bone marrow into the peripheral blood has been implicated in certain hematological disorders including various types of leukemia. In addition, accumulating evidence indicates that activation of NLRP3 plays a pivotal role in the development of transplant complications in patients receiving hematopoietic stem cell transplantation (HSCT) including graft versus host disease, severe infections, and transplant-related mortality. The majority of these complications are triggered by the severe tissue damage derived from the conditioning regimens utilized in HSCT which, in turn, activates NLRP3 and, ultimately, promotes the release of proinflammatory cytokines such as IL-1β and IL-18. Here, we summarize the implications of NLRP3 in HSCT with an emphasis on the involvement of this inflammasome component in transplant complications. Full article
(This article belongs to the Special Issue Molecular Immunology in Hematological Disorders)
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18 pages, 6242 KiB  
Review
Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia
by Fabio Forghieri, Giovanni Riva, Ivana Lagreca, Patrizia Barozzi, Francesca Bettelli, Ambra Paolini, Vincenzo Nasillo, Beatrice Lusenti, Valeria Pioli, Davide Giusti, Andrea Gilioli, Corrado Colasante, Laura Galassi, Hillary Catellani, Francesca Donatelli, Annalisa Talami, Rossana Maffei, Silvia Martinelli, Leonardo Potenza, Roberto Marasca, Enrico Tagliafico, Rossella Manfredini, Tommaso Trenti, Patrizia Comoli and Mario Luppiadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2021, 22(17), 9159; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179159 - 25 Aug 2021
Cited by 7 | Viewed by 4182
Abstract
The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms [...] Read more.
The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicating persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients. Full article
(This article belongs to the Special Issue Molecular Immunology in Hematological Disorders)
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Other

12 pages, 1638 KiB  
Case Report
Acute Neurological Involvement after Donor Lymphocyte Infusion for Post-Transplant Viral Infection: The Same Pattern of Novel Cancer Immunotherapy-Related CNS Toxicity?
by Annalisa Marcuzzi, Erika Rimondi, Elisabetta Melloni, Floriana Zennaro, Aurelio Sonzogni, Sara Leo and Natalia Maximova
Int. J. Mol. Sci. 2022, 23(7), 3553; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073553 - 24 Mar 2022
Cited by 1 | Viewed by 1654
Abstract
Early post-transplant is the critical phase for the success of hematopoietic stem cell transplantation (HSCT). New viral infections and the reactivations associated with complete ablation of the recipient’s T-cell immunity and inefficient reconstitution of the donor-derived system represent the main risks of HSCT. [...] Read more.
Early post-transplant is the critical phase for the success of hematopoietic stem cell transplantation (HSCT). New viral infections and the reactivations associated with complete ablation of the recipient’s T-cell immunity and inefficient reconstitution of the donor-derived system represent the main risks of HSCT. To date, the pharmacological treatments for post-HSCT viral infection-related complications have many limitations. Adoptive cell therapy (ACT) represents a new pharmacological strategy, allowing us to reconstitute the immune response to infectious agents in the post-HSC period. To demonstrate the potential advantage of this novel immunotherapy strategy, we report three cases of pediatric patients and the respective central nervous system complications after donor lymphocyte infusion. Full article
(This article belongs to the Special Issue Molecular Immunology in Hematological Disorders)
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