Postgrafting administration of granulocyte colony-stimulating factor impairs functional immune recovery in recipients of human leukocyte antigen haplotype–mismatched hematopoietic transplants

Blood ◽  
2001 ◽  
Vol 97 (8) ◽  
pp. 2514-2521 ◽  
Author(s):  
Isabella Volpi ◽  
Katia Perruccio ◽  
Antonella Tosti ◽  
Marusca Capanni ◽  
Loredana Ruggeri ◽  
...  
Keyword(s):  
T Cell ◽  
Human Leukocyte ◽  
Immune Reactivity ◽  
Immune Recovery ◽  
Cd4 Cells ◽  
Cell Reactivity ◽  
Leukocyte Antigen ◽  
Human Leukocyte Antigen Haplotype ◽  
T Cell Reactivity ◽  
Stimulating Factor

Abstract In human leukocyte antigen haplotype–mismatched transplantation, extensive T-cell depletion prevents graft-versus-host disease (GVHD) but delays immune recovery. Granulocyte colony-stimulating factor (G-CSF) is given to donors to mobilize stem cells and to recipients to ensure engraftment. Studies have shown that G-CSF promotes T-helper (Th)-2 immune deviation which, unlike Th1 responses, does not protect against intracellular pathogens and fungi. The effect of administration of G-CSF to recipients of mismatched hematopoietic transplants with respect to transplantation outcome and functional immune recovery was investigated. In 43 patients with acute leukemia who received G-CSF after transplantation, the engraftment rate was 95%. However, the patients had a long-lasting type 2 immune reactivity, ie, Th2-inducing dendritic cells not producing interleukin 12 (IL-12) and high frequencies of IL-4– and IL-10–producing CD4+ cells not expressing the IL-12 receptor β2 chain. Similar immune reactivity patterns were observed on exposure of donor cells to G-CSF. Elimination of postgrafting administration of G-CSF in a subsequent series of 36 patients with acute leukemia, while not adversely affecting engraftment rate (93%), resulted in the anticipated appearance of IL-12–producing dendritic cells (1-3 months after transplantation versus > 12 months in transplant recipients given G-CSF), of CD4+ cells of a mixed Th0/Th1 phenotype, and of antifungal T-cell reactivity in vitro. Moreover, CD4+ cell counts increased in significantly less time. Finally, elimination of G-CSF–mediated immune suppression did not significantly increase the incidence of GVHD (< 15%). Thus, this study found that administration of G-CSF to recipients of T-cell–depleted hematopoietic transplants was associated with abnormal antigen-presenting cell functions and T-cell reactivity. Elimination of postgrafting administration of G-CSF prevented immune dysregulation and accelerated functional immune recovery.

scholarly journals Haploidentical hematopoietic transplantation for the cure of leukemia: from its biology to clinical translation

Blood ◽  
2016 ◽  
Vol 128 (23) ◽  
pp. 2616-2623 ◽  
Author(s):  
Antonella Mancusi ◽  
Loredana Ruggeri ◽  
Andrea Velardi
Keyword(s):  
T Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Graft Versus Host ◽  
Haploidentical Transplantation ◽  
Hematopoietic Transplantation ◽  
Human Leukocyte Antigen Haplotype ◽  
Mother To Child

Abstract The present review describes the biology of human leukocyte antigen haplotype mismatched (“haploidentical”) transplantation, its translation to clinical practice to cure leukemia, and the results of current transplantation protocols. The 1990s saw what had been major drawbacks of haploidentical transplantation, ie, very strong host-versus-graft and graft-versus-host alloresponses, which led respectively to rejection and graft-versus-host disease (GVHD), being overcome through transplantation of a “mega-dose” of T cell–depleted peripheral blood hematopoietic progenitor cells and no posttransplant pharmacologic immunosuppression. The absence of posttransplant immunosuppression was an opportunity to discover natural killer cell alloreactions that eradicated acute myeloid leukemia and improved survival. Furthermore, it also unveiled the benefits of transplantation from mother donors, a likely consequence of the mother-to-child interaction during pregnancy. More recent transplantation protocols use unmanipulated (without ex vivo T-cell depletion) haploidentical grafts combined with enhanced posttransplant immunosuppression to help prevent GVHD. Unmanipulated grafts substantially extended the use of haploidentical transplantation with results than even rival those of matched hematopoietic transplantation. In T cell–depleted haploidentical transplantation, recent advances were made by the adoptive transfer of regulatory and conventional T cells.

Dissection of anti-CTLA4-induced cytotoxic T-cell responses in melanoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9078-9078
Author(s):  
John B. A. G. Haanen ◽  
Pia Kvistborg ◽  
Daisy Philips ◽  
Sander Kelderman ◽  
Bianca Heemskerk ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Cytotoxic T Cell ◽  
Clinical Activity ◽  
Immune Reactivity ◽  
Cell Detection ◽  
Cell Reactivity ◽  
Cell Responses ◽  
Cytotoxic T Cell Responses ◽  
T Cell Reactivity

9078 Background: There is strong evidence that melanoma-reactive T cells induced by immunotherapeutic interventions such as anti-CTLA4 therapy can exert clinically effects. However, there is very little information on how these therapies influence tumor-specific T cell responses. Furthermore, as the number of potential melanoma-associated antigens to which these responses can be directed is very high, classical strategies to map cytotoxic T cell reactivity do not suffice. Knowledge of such reactivities would be useful to design targeted strategies, selectively aiming to induce immune reactivity against these antigens. Methods: We have addressed these issues by designing MHC class I molecules occupied with UV-sensitive ‘conditional’ ligands, thereby allowing the production of very large collections of pMHC complexes for T cell detection. Secondly, we have developed a ‘combinatorial coding’ strategy that allows parallel detection of dozens of different T cell populations within a single sample. The combined use of MHC ligand exchange and combinatorial coding allows the high-throughput dissection of disease- and therapy-induced CTL immunity. We have used this platform to monitor immune reactivity against a panel of 145 melanoma-associated epitopes in patients receiving Ipilimumab treatment. Results: Comparison of PBMC samples from 32 melanoma patients pre- and post-therapy indicated a significant increase in the number of detectable melanoma-associated T cell responses (p=0.004). Furthermore, kinetic data on T cell responses during therapy suggests that this broadening generally occurs within weeks after start of therapy. The magnitude of melanoma-specific T cell responses that was detectable prior to start of therapy was not significantly altered (p=0.8). Conclusions: These results establish the pattern of melanoma-specific T-cell reactivity induced by anti-CTLA4 treatment and form a benchmark for evaluation of other immunotherapeutic interventions, like anti-PD1 treatment, that are currently undergoing clinical evaluation. Furthermore, our data suggests that the clinical activity of Ipilimumab may be mostly due to epitope spreading, rather than through enhancement of pre-existing immune activity.

scholarly journals T Cell Reactivity to Regulatory Factor X4 in Type 1 Narcolepsy

2021 ◽  
Author(s):  
Guo Luo ◽  
Selina Yogeshwar ◽  
Ling Lin ◽  
Emmanuel Mignot
Keyword(s):  
T Cell ◽  
Human Leukocyte ◽  
Autoimmune Disorder ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Regulatory Factor ◽  
Cell Reactivity ◽  
2009 H1n1 ◽  
T Cell Reactivity

Abstract Type 1 narcolepsy is strongly (98%) associated with human leukocyte antigen (HLA) class II DQA1*01:02/DQB1*06:02 (DQ0602) and highly associated with T cell receptor (TCR) alpha locus polymorphism as well as other immune regulatory loci. Increased incidence of narcolepsy was detected following the 2009 H1N1 pandemic and linked to Pandemrix ® vaccination, strongly supporting that narcolepsy is an autoimmune disorder. Although recent results suggest CD4+ T cell reactivity to neuropeptide hypocretin/orexin and cross-reactive flu peptide is involved, identification of other autoantigens has remained elusive. Here we study whether autoimmunity directed against Regulatory Factor X4 (RFX4), a protein co-localized with hypocretin, is involved in some cases. Studying human serum, we found that autoantibodies against RFX4 were rare. Using RFX4 peptides bound to DQ0602 tetramers, antigen RFX4-86,-95, and-60 specific human CD4+ T cells were detected in 4/10 patients and 2 unaffected siblings but not in others. Following culture with each cognate peptide, enriched autoreactive TCRαβ clones were isolated by single-cell sorting and TCR sequenced. Homologous clones bearing TRBV4-2 and recognizing RFX4-86 in patients and one twin control of patient were identified. These results suggest the involvement of RFX4 CD4+ T cell autoreactivity in some cases of narcolepsy.

scholarly journals Discriminative T cell recognition of cross-reactive islet-antigens is associated with HLA-DQ8 transdimer–mediated autoimmune diabetes

2019 ◽  
Vol 5 (8) ◽  
pp. eaaw9336
Author(s):  
I-Ting Chow ◽  
Theresa J. Gates ◽  
George K. Papadopoulos ◽  
Antonis K. Moustakas ◽  
Elizabeth M. Kolawole ◽  
...  
Keyword(s):  
T Cell ◽  
Autoimmune Diabetes ◽  
Human Leukocyte ◽  
In Silico Analysis ◽  
Cell Receptor ◽  
Cell Recognition ◽  
Cell Reactivity ◽  
T Cell Recognition ◽  
T Cell Reactivity ◽  
Hla Dqa1

Human leukocyte antigen (HLA)–DQ8 transdimer (HLA-DQA1*0501/DQB1*0302) confers exceptionally high risk in autoimmune diabetes. However, little is known about HLA-DQ8 transdimer–restricted CD4 T cell recognition, an event crucial for triggering HLA-DQ8 transdimer–specific anti-islet immunity. Here, we report a high degree of epitope overlap and T cell promiscuity between susceptible HLA-DQ8 and HLA-DQ8 transdimer. Despite preservation of putative residues for T cell receptor (TCR) contact, stronger disease-associated responses to cross-reactive, immunodominant islet epitopes are elicited by HLA-DQ8 transdimer. Mutagenesis at the α chain of HLA-DQ8 transdimer in complex with the disease-relevant GAD65250–266 peptide and in silico analysis reveal the DQ α52 residue located within the N-terminal edge of the peptide-binding cleft for the enhanced T cell reactivity, altering avidity and biophysical affinity between TCR and HLA-peptide complexes. Accordingly, a structurally promiscuous but nondegenerate TCR-HLA-peptide interface is pivotal for HLA-DQ8 transdimer–mediated autoimmune diabetes.

scholarly journals T cell reactivity to regulatory factor X4 in type 1 narcolepsy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Guo Luo ◽  
Selina Yogeshwar ◽  
Ling Lin ◽  
Emmanuel Jean-Marie Mignot
Keyword(s):  
T Cell ◽  
Human Leukocyte ◽  
Autoimmune Disorder ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Regulatory Factor ◽  
Cell Reactivity ◽  
Healthy Donors ◽  
T Cell Reactivity

AbstractType 1 narcolepsy is strongly (98%) associated with human leukocyte antigen (HLA) class II DQA1*01:02/DQB1*06:02 (DQ0602) and highly associated with T cell receptor (TCR) alpha locus polymorphism as well as other immune regulatory loci. Increased incidence of narcolepsy was detected following the 2009 H1N1 pandemic and linked to Pandemrix vaccination, strongly supporting that narcolepsy is an autoimmune disorder. Although recent results suggest CD4+ T cell reactivity to neuropeptide hypocretin/orexin and cross-reactive flu peptide is involved, identification of other autoantigens has remained elusive. Here we study whether autoimmunity directed against Regulatory Factor X4 (RFX4), a protein co-localized with hypocretin, is involved in some cases of narcolepsy. Studying human serum, we found that autoantibodies against RFX4 were rare. Using RFX4 peptides bound to DQ0602 tetramers, antigen RFX4-86, -95, and -60 specific human CD4+ T cells were detected in 4/10 patients and 2 unaffected siblings, but not in others. Following culture with each cognate peptide, enriched autoreactive TCRαβ clones were isolated by single-cell sorting and TCR sequenced. Homologous clones bearing TRBV4-2 and recognizing RFX4-86 in patients and one twin control of patient were identified. These results suggest the involvement of RFX4 CD4+ T cell autoreactivity in some cases of narcolepsy, but also in healthy donors.

scholarly journals Celiac Disease Revisited

2021 ◽  
pp. 1-14
Author(s):  
João Calado ◽  
Mariana Verdelho Machado
Keyword(s):  
Celiac Disease ◽  
Systemic Disease ◽  
Human Leukocyte ◽  
Risk Groups ◽  
Gluten Free Diet ◽  
Gluten Free ◽  
Serological Tests ◽  
Leukocyte Antigen ◽  
Human Leukocyte Antigen Haplotype ◽  
Circulating Autoantibodies

Celiac disease (CD) is a systemic disease triggered by gluten ingestion in genetically predisposed individuals. It manifests primarily as an autoimmune enteropathy associated with specific circulating autoantibodies and a human leukocyte antigen haplotype (HLA-DQ2 or HLA-DQ8). It afflicts roughly 1% of the population, though the majority of patients remain undiagnosed. Diarrhea and malabsorption are classic manifestations of CD; however, both children and adults can be paucisymptomatic and present extraintestinal manifestations such as anemia, osteoporosis, and abnormal liver tests. CD screening is not recommended for the general population, and it should be focused on high-risk groups. CD diagnosis is challenging and relies on serological tests, duodenal histology, and genetic testing. Particularly difficult presentations to manage are seronegative patients, seropositive patients without villus atrophy, and patients who have started a gluten-free diet before the diagnostic workup. The only proven treatment is a lifelong gluten-free diet. We present an in-depth review on the physiopathology and management of CD, with a particular emphasis on diagnostic challenges.

Duvelisib as bridge to allotransplantation in refractory peripheral T-cell lymphoma with T-follicular helper phenotype: case report

2021 ◽  
pp. 030089162110272
Author(s):  
Ginevra Lolli ◽  
Beatrice Casadei ◽  
Cinzia Pellegrini ◽  
Lisa Argnani ◽  
Federica Cocito ◽  
...  
Keyword(s):  
Case Report ◽  
T Cell ◽  
Human Leukocyte ◽  
Complete Response ◽  
Unrelated Donor ◽  
Phosphatidylinositol 3 Kinase ◽  
Leukocyte Antigen ◽  
Follicular Helper ◽  
T Cell Lymphomas ◽  
T Cell Malignancies

Objective: Peripheral T-cell lymphomas (PTCLs) are a group of heterogeneous T-cell malignancies representing 5%–10% of aggressive lymphomas. The prognosis is poor for patients with relapsed/refractory (R/R) disease, with a median overall survival of less than 6 months and no standardized treatments. We discuss the role of the phosphatidylinositol 3-kinase (PI3K) γδ inhibitor duvelisib as bridge to allotransplantation in a patient with R/R PTCL. Methods: Case report. Results: A 55-year-old woman diagnosed with relapsed nodal PTCL with T-follicular helper phenotype received PI3K γδ inhibitor duvelisib in the context of the phase II PRIMO clinical trial. After two cycles at a dose of 75 mg twice daily, the patient achieved complete response (CR), which was subsequently consolidated with human leukocyte antigen fully matched unrelated donor allotransplantation. No major toxicities were recorded during the duvelisib treatment period or during hospitalization for allotransplantation. At the latest follow-up, the patient was alive and still in CR 10 months posttransplant. Conclusions: Duvelisib should be further explored as a bridge to allotransplantation in patients with R/R PTCL, given the success and low toxicity in our patient.

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.

Sign in / Sign up

Export Citation Format

Share Document