scholarly journals HLA Alleles B*53:01 and C*06:02 Are Associated With Higher Risk of P. falciparum Parasitemia in a Cohort in Uganda

2021 ◽  
Vol 12 ◽  
Author(s):  
Jean C. Digitale ◽  
Perri C. Callaway ◽  
Maureen Martin ◽  
George Nelson ◽  
Mathias Viard ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cellular Immune Response ◽  
Hla Class I ◽  
T Cell Response ◽  
Class I ◽  
Hla Alleles ◽  
Symptomatic Malaria ◽  
Cellular Immune ◽  
Hla Molecules

Variation within the HLA locus been shown to play an important role in the susceptibility to and outcomes of numerous infections, but its influence on immunity to P. falciparum malaria is unclear. Increasing evidence indicates that acquired immunity to P. falciparum is mediated in part by the cellular immune response, including NK cells, CD4 and CD8 T cells, and semi-invariant γδ T cells. HLA molecules expressed by these lymphocytes influence the epitopes recognized by P. falciparum-specific T cells, and class I HLA molecules also serve as ligands for inhibitory receptors including KIR. Here we assessed the relationship of HLA class I and II alleles to the risk of P. falciparum infection and symptomatic malaria in a cohort of 892 Ugandan children and adults followed prospectively via both active and passive surveillance. We identified two HLA class I alleles, HLA-B*53:01 and HLA-C*06:02, that were associated with a higher prevalence of P. falciparum infection. Notably, no class I or II HLA alleles were found to be associated with protection from P. falciparum parasitemia or symptomatic malaria. These findings suggest that class I HLA plays a role in the ability to restrict parasitemia, supporting an essential role for the cellular immune response in P. falciparum immunity. Our findings underscore the need for better tools to enable mechanistic studies of the T cell response to P. falciparum at the epitope level and suggest that further study of the role of HLA in regulating pre-erythrocytic stages of the P. falciparum life cycle is warranted.

scholarly journals Predicted Epitope Abundance Supports Vaccine-Induced Cytotoxic Protection Against SARS-CoV-2 Variants of Concern

2021 ◽  
Vol 12 ◽  
Author(s):  
Antonio J. Martín-Galiano ◽  
Francisco Díez-Fuertes ◽  
Michael J. McConnell ◽  
Daniel López
Keyword(s):  
Immune Response ◽  
Vaccine Efficacy ◽  
Cellular Immune Response ◽  
Hla Class I ◽  
Computational Prediction ◽  
Class I ◽  
Immune Protection ◽  
Critical Importance ◽  
Potential Impact ◽  
Cellular Immune

The effect of emerging SARS-CoV-2 variants on vaccine efficacy is of critical importance. In this study, the potential impact of mutations that facilitate escape from the cytotoxic cellular immune response in these new virus variants for the 551 most abundant HLA class I alleles was analyzed. Computational prediction showed that most of these alleles, that cover >90% of the population, contain enough epitopes without escape mutations in the principal SARS-CoV-2 variants. These data suggest that the cytotoxic cellular immune protection elicited by vaccination is not greatly affected by emerging SARS-CoV-2 variants.

Generation and Characterization Of a Third Party GMP Grade Bank Of CMV Specific T-Cells For Adoptive Immunotherapy Of CMV Infections In Recipients Of HSCT From Cord Blood Or Seronegative Donors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2021-2021
Author(s):  
Aisha N. Hasan ◽  
Ekaterina Doubrovina ◽  
Guenther Koehne ◽  
Susan E. Prockop ◽  
Richard J. O'Reilly
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Cell Response ◽  
Hla Class I ◽  
T Cell Response ◽  
Third Party ◽  
Class I ◽  
Hla Alleles ◽  
Ctl Responses

Abstract Adoptive transfer of virus-specific T-cells (CTLs) derived from allogeneic HLA partially matched third party donors can also be effective in a proportion of patients developing EBV lymphomas, or infections due to CMV or adenovirus following transplants from seronegative donors. Such third party donor derived CTLs offer an off the shelf reagent for treatment of viral infections developing after transplant. However, the immunodominant cytotoxic activity exhibited by the CTLs is directed against specific epitopes of the viral protein and restricted by 1-2 HLA alleles. Therefore, it is critical that the T-cells administered from third party donors can recognize viral epitopes presented on shared HLA alleles. We have established a bank of 119 CMV specific T-cell lines (CMV CTLs) generated using autologous APCs loaded with a pool of overlapping peptides spanning the sequence of the dominant immunogenic protein CMVpp65. Each of these 119 CMV CTL lines has been characterized as to the epitope inducing T-cell response as well as the HLA allele restricting the epitope specific T-cell response. Epitopes were identified using an overlapping grid of peptide pools and the HLA restriction by cytotoxic activity against peptide loaded EBVBLCLs matched at a single HLA allele with the T-cell donor. The distribution of the common HLA alleles among the donors for these CTL lines was predominantly within the distribution of HLA allele frequencies represented in the caucasian and black populations, except for HLA A0201 and B0702, which were over represented ( 33% vs 25% and 21% vs 8.7% respectively). In 54% of the CTL lines, the immunodominant T-cell responses were restricted by HLA A0201 (25%), B0702 (21%) and B 3501-11(8%), and in the remaining 50%, the responses were restricted by other HLA class-I alleles, while only 16/119 lines (13%) were restricted by HLA class-II alleles. All 25 donors inheriting HLA B0702 (25/25) demonstrated HLA B0702 restricted CMV CTL responses, while 30/39 (77%) donors inheriting HLA A0201 and 9/19 (47%) donors inheriting HLA B3501-11 demonstrated HLA A0201 and B3501-11 restricted CMV CTL responses. Among all 9 donors co-inheriting HLA A0201 and B 0702, the immunodominant T-cell response was restricted by B0702. Among 12 donors co-inheriting A0201 and B 4401-04, 11/12 (91.6%) demonstrated immunodominant CMV CTL responses restricted by A0201; 1 donor also co-inherited HLA B0702 whose response was restricted by B0702. Therefore, an immunodominance hierarchy for HLA class-I alleles presenting the dominant CMVpp65 epitope was evident through this analysis among these 119 donors and was as follows: B 0702, A0201, B3501-11, A2601, B44, B40, B4201, A0101, B 1801. Strikingly, only 1 of 119 donors demonstrated T-cell responses restricted by A1101; a commonly inherited HLA class –I allele. In a series of 239 consecutive HLA matched related or unrelated transplants (MUD) and 137 HLA mismatched unrelated (MMUD) transplants, and 100 cord blood transplants conducted at our center, in 86%, 89% and 80% of the cases respectively, we could identify a CMV CTL line restricted by a shared HLA allele and matched at 2-3 alleles within this GMP grade CTL bank that would be immediately available for treatment of CMV infection. Appropriately restricted CMV CTLs would only be available in 60-70% of MMUD transplant and none of the cord blood transplants without this approach. This CMV CTL bank therefore represents a readily available clinical reagent for the treatment of resistant CMV infections developing in post transplant patients. The characterization of the CTLs has also enabled the further elucidation of immunodominant CMVpp65 epitopes and hierarchies. Since we have previously shown that CMV CTLs can be generated against subdominant epitopes presented by both common HLA alleles as well as less prevalent HLA alleles using a panel of artificial antigen presenting cells (AAPCs), expansion of this bank using T-cell sensitized against CMVpp65 presented on such AAPCs should broaden the applicability of this bank to all HSCT recipients. Disclosures: No relevant conflicts of interest to declare.

Kinetics of the pregnancy-induced humoral and cellular immune response against the paternal HLA class I antigens of the child

2002 ◽  
Vol 63 (6) ◽  
pp. 452-458 ◽  
Author(s):  
Corine A. van Kampen ◽  
Minke F.J. Versteeg-vd Voort Maarschalk ◽  
Janneke Langerak-Langerak ◽  
Dave L. Roelen ◽  
Frans H.J. Claas
Keyword(s):  
Immune Response ◽  
Cellular Immune Response ◽  
Hla Class I ◽  
Class I ◽  
Hla Class I Antigens ◽  
Cellular Immune ◽  
Kinetics Of

Differential Immunogenicity of HLA Class I Alloantigens for the Humoral versus the Cellular Immune Response: “Towards Tailor-Made HLA Mismatching”

2006 ◽  
Vol 67 (6) ◽  
pp. 424-429 ◽  
Author(s):  
Frans H.J. Claas ◽  
Dave L. Roelen ◽  
Arend Mulder ◽  
Ilias I.N. Doxiadis ◽  
Machteld Oudshoorn ◽  
...  
Keyword(s):  
Immune Response ◽  
Cellular Immune Response ◽  
Hla Class I ◽  
Class I ◽  
Cellular Immune

scholarly journals Immunosequencing and epitope mapping reveal substantial preservation of the T cell immune response to Omicron generated by SARS-CoV-2 vaccines

2021 ◽  
Author(s):  
Damon H. May ◽  
Benjamin E. R. Rubin ◽  
Sudeb C. Dalai ◽  
Krishna Patel ◽  
Shahin Shafiani ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cellular Immune Response ◽  
Epitope Mapping ◽  
Protective Efficacy ◽  
T Cell Response ◽  
Cell Immune Response ◽  
Cell Immunity ◽  
Cellular Immune

The Omicron SARS-CoV-2 variant contains 34 mutations in the spike gene likely impacting protective efficacy from vaccines. We evaluated the potential impact of these mutations on the cellular immune response. Combining epitope mapping to SARS-CoV-2 vaccines that we have determined from past experiments along with T cell receptor (TCR) repertoire sequencing from thousands of vaccinated or naturally infected individuals, we estimate the abrogation of the cellular immune response in Omicron. Although 20% of CD4+ T cell epitopes are potentially affected, the loss of immunity mediated by CD4+ T cells is estimated to be slightly above 30% as some of the affected epitopes are relatively more immunogenic. For CD8+ T cells, we estimate a loss of approximately 20%. These reductions in T cell immunity are substantially larger than observed in other widely distributed variants. Combined with the expected substantial loss of neutralization from antibodies, the overall protection provided by SARS-CoV-2 vaccines could be impacted adversely. From analysis of prior variants, the efficacy of vaccines against symptomatic infection has been largely maintained and is strongly correlated with the T cell response but not as strongly with the neutralizing antibody response. We expect the remaining 70% to 80% of on-target T cells induced by SARS-CoV-2 vaccination to reduce morbidity and mortality from infection with Omicron.

Analysis of Memory T Lymphocytes Activity Following Stimulation with HLA-A24, A1 and Cw4 Restricted 9- and 10-mer Cytomegalovirus pp65 Overlapping Peptides.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2876-2876
Author(s):  
Monica Ghei ◽  
David F. Stroncek ◽  
Maurizio Provenzano
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Immune Therapy ◽  
Hla Class I ◽  
Class I ◽  
Specific Ctls ◽  
Over Time

Abstract In healthy subjects, primary infection with Cytomegalovirus (CMV) is usually mild or asymptomatic and is effectively controlled by the cell-mediated immune response. However, in immune compromised individuals, such as those with AIDS or after bone marrow transplantation, CMV reactivation is associated with significant morbidity until the individual’s immune system is completely reconstituted. One means of preventing post-transplant CMV infection is adoptive immunotherapy using CMV-specific cytotoxic T cells (CTLs) from the transplant donor. Several 9- and 10-mer HLA class I restricted peptides derived from the immune dominant CMV 65 kd matrix phosphoprotein (pp65) have been shown to produce CMV-specific CTLs. Two overlapping HLA-A24 restricted peptides have been specifically described: pp65 341–349 and pp65 341–350. These are 9- and 10-mer peptides that overlap except for the last amino acid phenylalanine (F) at the C-terminus [QYDPVAALF(F)]. Despite their similarity, the ability of these peptides to induce a T cell response has been reported to differ. Although it has been generally accepted that a unique CMV peptide is bound and presented by each separate HLA class I molecule, recent studies suggest that certain peptides are more promiscuous and may be presented by more than one HLA Class I antigen. For example, the 9-mer pp65 341–349 has been shown to stimulate CTLs from both HLA-A24 and Cw4 donors, while the 10-mer pp65 341–350 has been shown to be reactive with both HLA-A24 and A1 donors. The current investigation sought to compare the potency of these two peptides and determine the optimum peptide size for effective CMV adoptive immune therapy. Both peptides were tested for their ability to stimulate CMV-specific CTLs in HLA-A24, HLA-A1, and HLA-Cw4 restriction. In addition, a pp65 16-mer that included the 9- and 10-mers was tested for its ability to reactivate either CD8+ or CD4+ memory T cells. IFN-γ mRNA transcript as well as protein production were measured by in vitro cell culture assays. Peptide stimulations were performed on isolated CD8 and CD4 T lymphocytes by inducing the cells for 3 hours after a 2-week in vitro sensitization. The goal of the investigation was to determine whether both the 9- and the 10-mer peptides maintained high levels of CTL stimulation over time for all HLA restrictions studied. Moreover, it was important to investigate whether stimulation with the 16-mer, followed by restimulation by the two smaller peptides embedded within the larger sequence, led to effective T cell memory immune response. The 9- and 10-mer peptides effectively stimulated CTLs from HLA-A24, HLA-A1, and HLA-Cw4 CMV seropositive donors. Although both 9- and 10-mer were able to maintain high levels of stimulation over time for all restrictions, the 9-mer induced highest responses in cells expressing HLA-A24 (S.I. 4.07–528) or HLA-Cw4 (S.I. 4.15–483) while the 10-mer induced highest responses in cells expressing HLA-A24 (S.I. 3.5–528) or HLA-A1 (S.I. 8.25–615). The 16-mer peptide was also able to stimulate T cells from all HLA-A24, A1 and Cw4 donors (S.I. 6.95, 4.96, 5.02) at levels that are well maintained over time. This data confirmed that both the 9- and the 10-mer peptides are promiscuous and not restricted to a single HLA antigen. These peptides that have the ability to produce CMV-specific CTLs in patients with several different HLA types present a practical advantage over peptides that are restricted only to a single HLA type, and thus are optimal for CMV adoptive immune therapy.

Leukemic Blasts Acting as Host Antigen Presenting Cells Trigger a Combined CD4 and CD8 Allo-Immune Response Directed Against Mismatched HLA Class I.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5030-5030
Author(s):  
Avital Amir ◽  
Renate S. Hagendoorn ◽  
Erik W.A. Marijt ◽  
Roelof Willemze ◽  
J.H. Frederik Falkenburg ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Hla Class I ◽  
Cd8 T Cell ◽  
Class I ◽  
Mixed Chimerism ◽  
Target Cells ◽  
Hla Dr ◽  
Donor T Cells

Abstract Single HLA locus mismatched stem cell transplantation (SCT) is applied in patients with hematological malignancies who may benefit from allogeneic transplantation but lack an HLA-matched donor. Although HLA disparity between patient and donor increases the risk of developing GVHD, the relative risk of GVHD after single HLA locus mismatched SCT is only 1.5 fold. In view of the high frequency of allo-HLA reactive T-cells, which is about 1000-fold higher than the frequencies of minor histocompatibility antigen specific T-cells, this risk increase is lower than could be expected. Since almost all nucleated cells express HLA class I, one would expect all single HLA class I mismatched transplanted patients to develop severe GVHD. We hypothesized therefore that the presentation of the HLA class I mismatched allele on nucleated cells of the patient is not sufficient to elicit an effective allo-immune response. We characterized the allo-immune response in a patient with acute myeloid leukemia (AML) who was treated with a T-cell depleted SCT from a sibling donor who was HLA identical except for an HLA-A2 crossover. Six months after SCT, donor lymphocyte infusion (DLI) of 2.5*10e6 T-cells/kg was given for mixed chimerism comprising 99% T-cells of patient origin. No clinical response and no GVHD developed. Twelve months after SCT 95% of T-cells were still of patient origin, and AML relapse occurred with 9% blasts in bone marrow for which a second DLI containing 7.5*10e6 T-cells/kg was given. Five weeks after the DLI the patient died of grade IV GVHD. During the GVHD, conversion to donor chimerism developed. In peripheral blood of the patient 90% of CD8 and 40% of CD4 donor T-cells were activated as determined by HLA-DR expression. To analyze the nature of the immune response, the activated CD8 and CD4 donor T-cells were single cell sorted, expanded and tested for alloreactivity and HLA restriction using cytotoxicity and cytokine production assays against a panel of target cells blocked with different HLA-mAbs. 82% of the CD8 T-cell clones were alloreactive and restricted to the allo-HLA-A2. The response was highly polyclonal as shown by the usage of different T-cell receptor Vβ chains with different CDR3 sequences. 26% of the CD4 clones were alloreactive and this response was also polyclonal. The CD4 clones were HLA-DR1 restricted and recognized donor EBV-LCL transduced with HLA-A2, indicating that the peptide recognized in HLA-DR1 was derived from the mismatched HLA-A2 molecule. The recognized epitope was demonstrated to comprise AA 103–120 derived from a hypervariable region of HLA-A2. At the time of the first DLI, only HLA class I expressing T-cells and non-hematopoietic patient derived cells were present, capable of activating the CD8 T-cells but not of triggering the CD4 response. Leukemic blasts present at the time of the second DLI, however, expressed both HLA-DR and HLA class I, and were shown to activate the CD4 as well as the CD8 clones. We hypothesize that the HLA class II expression on hematopoietic cells of the patient at the time of the relapse was essential for the development of this immune response. In conclusion, these results indicate a role for patient leukemic blasts acting as host APCs in initiating the GVH response by activating both a CD4 and CD8 T-cell response in an HLA class I mismatched setting.

Thrombocyte HLA molecules retain nonrenewable endogenous peptides of megakaryocyte lineage and do not stimulate direct allocytotoxicity in vitro

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3168-3175
Author(s):  
Cécile Gouttefangeas ◽  
Marianne Diehl ◽  
Wieland Keilholz ◽  
Rainer Frank Hörnlein ◽  
Stefan Stevanović ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Hla Class I ◽  
T Cell Response ◽  
Third Party ◽  
Class I ◽  
Cytotoxic T Cell ◽  
Endogenous Peptides ◽  
Hla Class I Molecules ◽  
Hla Molecules

The origin and the function of HLA class I molecules present on the surface of human platelets are still unclear. In particular, it is controversial which fraction of these class I molecules represents integral membrane components derived from the megakaryocyte-platelet lineage versus soluble plasma HLA molecules acquired by adsorption. Results of the present study show that HLA-A2 ligands isolated from platelets possess the same peptide motif as described for HLA-A2-associated peptides obtained from nucleated cells. Sequencing of these platelet-derived peptides reveals that they originate mainly from ubiquitously expressed proteins also present in the megakaryocyte-platelet lineage. Moreover, one of these peptides derives from the GPIX protein, which is specifically expressed by platelets and their precursors. Platelet HLA molecules are unstable in vitro at 37°C, but can be partially stabilized by addition of exogenous β2-microglobulin and HLA class I binding peptide, suggesting that platelets cannot load HLA molecules with endogenous peptides. In in vitro experiments platelets were used to stimulate peripheral blood mononuclear cells. No allospecific cytotoxicity was observed after primary stimulation, or secondary restimulation, with allogenic resting or activated platelets, even in the presence of additional third-party helper activity. These data indicate that HLA class I molecules from platelets cannot directly induce allogenic CD8+ cytotoxic T-cell response in vitro.

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