scholarly journals γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

2021 ◽  
Vol 12 ◽  
Author(s):  
Mateus de Souza Barros ◽  
Nilberto Dias de Araújo ◽  
Fábio Magalhães-Gama ◽  
Thaís Lohana Pereira Ribeiro ◽  
Fabíola Silva Alves Hanna ◽  
...  
Keyword(s):  
T Cells ◽  
Γδ T Cells ◽  
Human Leukocyte ◽  
Lymphocyte Subpopulation ◽  
Complex Nature ◽  
Promising Alternative ◽  
Leukocyte Antigen ◽  
Cell Mediated Immune Response ◽  
Wide Range ◽  
T Cell Engineering

Recently, many discoveries have elucidated the cellular and molecular diversity in the leukemic microenvironment and improved our knowledge regarding their complex nature. This has allowed the development of new therapeutic strategies against leukemia. Advances in biotechnology and the current understanding of T cell-engineering have led to new approaches in this fight, thus improving cell-mediated immune response against cancer. However, most of the investigations focus only on conventional cytotoxic cells, while ignoring the potential of unconventional T cells that until now have been little studied. γδ T cells are a unique lymphocyte subpopulation that has an extensive repertoire of tumor sensing and may have new immunotherapeutic applications in a wide range of tumors. The ability to respond regardless of human leukocyte antigen (HLA) expression, the secretion of antitumor mediators and high functional plasticity are hallmarks of γδ T cells, and are ones that make them a promising alternative in the field of cell therapy. Despite this situation, in particular cases, the leukemic microenvironment can adopt strategies to circumvent the antitumor response of these lymphocytes, causing their exhaustion or polarization to a tumor-promoting phenotype. Intervening in this crosstalk can improve their capabilities and clinical applications and can make them key components in new therapeutic antileukemic approaches. In this review, we highlight several characteristics of γδ T cells and their interactions in leukemia. Furthermore, we explore strategies for maximizing their antitumor functions, aiming to illustrate the findings destined for a better mobilization of γδ T cells against the tumor. Finally, we outline our perspectives on their therapeutic applicability and indicate outstanding issues for future basic and clinical leukemia research, in the hope of contributing to the advancement of studies on γδ T cells in cancer immunotherapy.

T Cells: A Growing Universe of Roles in Neurodegenerative Diseases

2021 ◽  
pp. 107385842110249
Author(s):  
Dallin Dressman ◽  
Wassim Elyaman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Neurodegenerative Diseases ◽  
Human Leukocyte ◽  
Autoimmune Response ◽  
Antigen Specificity ◽  
Risk Genes ◽  
Leukocyte Antigen ◽  
Histocompatibility Complex ◽  
The Central Nervous System

T cells play a central role in homeostasis and host defense against infectious diseases. T cell dysregulation can lead to recognizing self-antigens as foreign antigens, causing a detrimental autoimmune response. T cell involvement in multiple sclerosis (MS), long understood to be an autoimmune-mediated neurodegenerative disease, is well characterized. More recently, a role for T cells has also been identified for the neurodegenerative diseases Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Interestingly, several alleles and variants of human leukocyte antigen (HLA) genes have been classified as AD and PD risk genes. HLA codes for components of major histocompatibility complex (MHC) class I or class II, both of which are expressed by microglia, the innate immune cells of the central nervous system (CNS). Thus, both microglia and T cells may potentially interact in an antigen-dependent or independent fashion to shape the inflammatory cascade occurring in neurodegenerative diseases. Dissecting the antigen specificity of T cells may lead to new options for disease-modifying treatments in neurodegenerative diseases. Here, we review the current understanding of T cells in neurodegenerative diseases. We summarize the subsets of T cells, their phenotype and potential functions in animal models and in human studies of neurodegenerative diseases.

scholarly journals Graft failure after T-cell-depleted human leukocyte antigen identical marrow transplants for leukemia: I. Analysis of risk factors and results of secondary transplants

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2227-2236 ◽  
Author(s):  
NA Kernan ◽  
C Bordignon ◽  
G Heller ◽  
I Cunningham ◽  
H Castro-Malaspina ◽  
...  
Keyword(s):  
Risk Factors ◽  
T Cells ◽  
T Cell ◽  
Human Leukocyte Antigen ◽  
Graft Failure ◽  
Human Leukocyte ◽  
Marrow Transplant ◽  
High Dose ◽  
Leukocyte Antigen ◽  
Major Factors

Abstract Risk factors for graft failure were analyzed in 122 recipients of an allogeneic T-cell-depleted human leukocyte antigen (HLA)-identical sibling marrow transplant as treatment for leukemia. In each case pretransplant immunosuppression included 1,375 to 1,500 cGy hyperfractionated total body irradiation and cyclophosphamide (60 mg/kg/d x 2). No patient received immunosuppression prosttransplant for graft-versus-host disease (GVHD) prophylaxis. Nineteen patients in this group experienced graft failure. The major factors associated with graft failure were transplants from male donors and the age of the patient (or donor). Among male recipients of male donor-derived grafts a low dose per kilogram of nucleated cells, progenitor cells (colony forming unit-GM) and T cells was also associated with graft failure. Additional irradiation to 1,500 cGy, high dose corticosteroids posttransplant, and additional peripheral blood donor T cells did not decrease the incidence of graft failure. In addition, type of leukemia, time from diagnosis to transplant, an intact spleen, or the presence of antidonor leukocyte antibodies did not correlate with graft failure. To ensure engraftment of secondary transplants, further immunosuppression was necessary but was poorly tolerated. However, engraftment and survival could be achieved with an immunosuppressive regimen in which antithymocyte globulin and high dose methylprednisolone were administered both before and after infusions of secondary partially T- cell-depleted marrow grafts.

scholarly journals Mixed chimerism and acceptance of kidney transplants after immunosuppressive drug withdrawal

2020 ◽  
Vol 12 (528) ◽  
pp. eaax8863 ◽  
Author(s):  
Stephan Busque ◽  
John D. Scandling ◽  
Robert Lowsky ◽  
Judith Shizuru ◽  
Kent Jensen ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Drug Withdrawal ◽  
Human Leukocyte ◽  
Immunosuppressive Drug ◽  
Mixed Chimerism ◽  
Leukocyte Antigen ◽  
Donor Cells ◽  
Tacrolimus Therapy ◽  
B Cell Precursors

Preclinical studies have shown that persistent mixed chimerism is linked to acceptance of organ allografts without immunosuppressive (IS) drugs. Mixed chimerism refers to continued mixing of donor and recipient hematopoietic cells in recipient tissues after transplantation of donor cells. To determine whether persistent mixed chimerism and tolerance can be established in patients undergoing living donor kidney transplantation, we infused allograft recipients with donor T cells and hematopoietic progenitors after posttransplant lymphoid irradiation. In 24 of 29 fully human leukocyte antigen (HLA)–matched patients who had persistent mixed chimerism for at least 6 months, complete IS drug withdrawal was achieved without subsequent evidence of rejection for at least 2 years. In 10 of 22 HLA haplotype–matched patients with persistent mixed chimerism for at least 12 months, reduction of IS drugs to tacrolimus monotherapy was achieved. Withdrawal of tacrolimus during the second year resulted in loss of detectable chimerism and subsequent rejection episodes, unless tacrolimus therapy was reinstituted. Posttransplant immune reconstitution of naïve B cells and B cell precursors was more rapid than the reconstitution of naïve T cells and thymic T cell precursors. Robust chimerism was observed only among naïve T and B cells but not among memory T cells. No evidence of rejection was observed in all surveillance graft biopsies obtained from mixed chimeric patients withdrawn from IS drugs, and none developed graft-versus-host disease. In conclusion, persistent mixed chimerism established in fully HLA- or haplotype-matched patients allowed for complete or partial IS drug withdrawal without rejection.

Allogeneic transplantation of CD34+selected cells from peripheral blood from human leukocyte antigen–identical siblings: detrimental effect of a high number of donor CD34+ cells?

Blood ◽  
2001 ◽  
Vol 98 (8) ◽  
pp. 2352-2357 ◽  
Author(s):  
Alvaro Urbano-Ispizua ◽  
Enric Carreras ◽  
Pedro Marı́n ◽  
Montserrat Rovira ◽  
Carmen Martı́nez ◽  
...  
Keyword(s):  
T Cells ◽  
Clinical Outcome ◽  
Human Leukocyte Antigen ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Early Stage ◽  
Human Leukocyte ◽  
Optimum Number ◽  
Leukocyte Antigen ◽  
Cd34 Cells

Clinical results after T-cell–depleted allografts might be improved by modifying the graft content of progenitor and accessory cells. Although the association of the number of donor T cells with the clinical outcome has been studied extensively, the optimum number of progenitor cells that should be administered to patients is unknown. The characteristics of 84 consecutive human leukocyte antigen (HLA)–identical sibling transplants of granulocyte colony-stimulating factor (G-CSF)–mobilized peripheral blood progenitor cells depleted of T cells by CD34+ positive selection (allo-PBT/CD34+) were analyzed for their effect on clinical outcome. After a median follow-up of 24 months (range, 1-70 months), 50 patients remain alive (59.5%) and 34 have died (21 [25%] as a result of the transplant and 13 [15.5%] due to disease relapse). The median number of CD34+ cells administered to the patients was 3.9 × 106/kg (range, 1.2-14.3 × 106/kg). A number of CD34+ cells in the inoculum of 1 × 106/kg to 3 × 106/kg was associated with increased survival: 21 of 28 (75%) patients are alive, as compared with 29 of 56 (52%) patients receiving more than 3 × 106/kg (actuarial probability 75% vs. 42%, respectively; P = .01). In the multivariate analysis, the independent prognostic variables for survival were CD34+cell dose 1 × 106/kg to 3 × 106/kg (RR = 4.8; P = .0008), sex-pairing match (RR = 3.2;P = .002), and early stage of disease (RR = 2.8;P = .007). From these results it appears that, in allo-PBT/CD34+ from HLA-identical siblings, a number of CD34+ cells in the inoculum between 1 × 106/kg to 3 × 106/kg is an important factor for better survival, and that higher CD34+ cell doses might be associated with a poorer outcome.

scholarly journals Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma

Blood ◽  
2011 ◽  
Vol 117 (3) ◽  
pp. 788-797 ◽  
Author(s):  
Aaron P. Rapoport ◽  
Nicole A. Aqui ◽  
Edward A. Stadtmauer ◽  
Dan T. Vogl ◽  
Hong-Bin Fang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Leukocyte Antigen ◽  
Conjugate Vaccine ◽  
Tumor Antigen ◽  
Pneumococcal Conjugate Vaccine ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Cell Counts ◽  
Antigen Vaccine

AbstractIn a phase 1/2 two-arm trial, 54 patients with myeloma received autografts followed by ex vivo anti-CD3/anti-CD28 costimulated autologous T cells at day 2 after transplantation. Study patients positive for human leukocyte antigen A2 (arm A, n = 28) also received pneumococcal conjugate vaccine immunizations before and after transplantation and a multipeptide tumor antigen vaccine derived from the human telomerase reverse transcriptase and the antiapoptotic protein survivin. Patients negative for human leukocyte antigen A2 (arm B, n = 26) received the pneumococcal conjugate vaccine only. Patients exhibited robust T-cell recoveries by day 14 with supraphysiologic T-cell counts accompanied by a sustained reduction in regulatory T cells. The median event-free survival (EFS) for all patients is 20 months (95% confidence interval, 14.6-24.7 months); the projected 3-year overall survival is 83%. A subset of patients in arm A (36%) developed immune responses to the tumor antigen vaccine by tetramer assays, but this cohort did not exhibit better EFS. Higher posttransplantation CD4+ T-cell counts and a lower percentage of FOXP3+ T cells were associated with improved EFS. Patients exhibited accelerated polyclonal immunoglobulin recovery compared with patients without T-cell transfers. Adoptive transfer of tumor antigen vaccine-primed and costimulated T cells leads to augmented and accelerated cellular and humoral immune reconstitution, including antitumor immunity, after autologous stem cell transplantation for myeloma. This study was registered at www.clinicaltrials.gov as NCT00499577.

scholarly journals Increased CD69 and Human Leukocyte Antigen-DR Expression on T Lymphocytes in Insulin-Dependent Diabetes Mellitus of Long Standing

1998 ◽  
Vol 83 (6) ◽  
pp. 2204-2209 ◽  
Author(s):  
Alois Gessl ◽  
Werner Waldhäusl
Keyword(s):  
Diabetes Mellitus ◽  
T Cells ◽  
Human Leukocyte ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Leukocyte Antigen ◽  
Hla Dr ◽  
Insulin Dependent

To better define prevailing activation of circulating T cell subsets in insulin-dependent diabetes mellitus (IDDM) of recent onset (DM; n= 31; median age ± sd,, 28 ± 6.9 yr) and of long standing (DML; n = 27; age, 33 ± 10.4 yr; median duration of disease, 105 months), CD4+ and CD8+ T cells were analyzed to determine their naive and memory subsets as well as their expression of human leukocyte antigen (HLA)-DR, interleukin-2 receptor α-chain (CD25), and CD69 by three-color flow cytometry. Twenty-six healthy subjects (HS; age, 32.0 ± 8.2 yr) served as controls. No deviation was seen in either IDDM group compared to HS in CD25 expression on CD4+ or CD8+ cells or in their CD45RA+ or CD45RA− subsets. HLA-DR expression, however, was increased (P < 0.05) in total CD8+ cells and CD45RA+ cells, with CD45RA− CD8+ cells joining the prevailing pattern only in DML. Among CD4+ cells, increased expression of HLA-DR molecules was restricted to total and CD45RA− cells in DML. CD69 expression did not differ between IDDM and HS, but differed between DML (CD4+, CD8+, and CD45RA− CD4+) and DM only. In conclusion, our data demonstrate that HLA-DR expression in IDDM is restricted to memory cells (CD45RA−) among CD4+ cells in DML and is more markedly confined to naive (CD45RA+) than to memory CD8+ cells, whereas the early activation antigen CD69 is more readily expressed in DML than in DM. The observed activation of circulating T cells suggests an ongoing immune process in IDDM both at clinical manifestation and after long duration.

scholarly journals A suppressor T cell of the mixed lymphocyte reaction in man specific for the stimulating alloantigen. Evidence that identity at HLA-D between suppressor and responder is required for suppression.

1978 ◽  
Vol 147 (1) ◽  
pp. 137-146 ◽  
Author(s):  
E G Engleman ◽  
A J McMichael ◽  
M E Batey ◽  
H O McDevitt
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Leukocyte Antigen ◽  
Gamma Irradiation ◽  
Mixed Lymphocyte Reaction ◽  
Suppressor Cells ◽  
Human Leukocyte ◽  
Multiparous Woman ◽  
Leukocyte Antigen ◽  
Suppressor T Cell

It has previously been shown that J.H., a human leukocyte antigen (HLA)-Dw2 homozygous multiparous woman, fails to respond in a mixed lymphocyte reaction (MLR) to her Dw1 homozygous husband W.H., and that her T cells suppress the responses of HLA matched responders to W.H. The present studies take advantage of the observation that J.H. suppressor cells resist a dose of gamma-irradiation which functionally eliminates her MLR responder cells. J.H. cells, depleted of alloreactive cells, suppress the responses of Dw2 heterozygous or homozygous cells to W.H., regardless of their associated HLA-A or B antigens. Only when W.H. or a few other cells are present as the irradiated stimulator is J.H. suppression of Dw2 responses detected. Thus, the J.H. suppressor T cell recognizes determinants in the irradiated stimulator cells as well as D locus products in the responder.

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