Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients

Blood ◽  
2002 ◽  
Vol 99 (4) ◽  
pp. 1442-1448 ◽  
Author(s):  
Susanne Auffermann-Gretzinger ◽  
Izidore S. Lossos ◽  
Tamara A. Vayntrub ◽  
Wendy Leong ◽  
F. Carl Grumet ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Hematopoietic Cell ◽  
Steady Increase ◽  
Cell Transplant ◽  
Allogeneic Hct

Regeneration of hematopoiesis after allogeneic hematopoietic cell transplantation (HCT) involves conversion of the recipient's immune system to donor type. It is likely that distinct cell lineages in the recipient reconstitute at different rates. Dendritic cells (DCs) are a subset of hematopoietic cells that function as a critical component of antigen-specific immune responses because they modulate T-cell activation, as well as induction of tolerance. Mature DCs are transferred with hematopoietic grafts and subsequently arise de novo. Little information exists about engraftment kinetics and turnover of this cell population in patients after allogeneic HCT. This study examined the kinetics of DC chimerism in patients who underwent matched sibling allogeneic HCT. T-cell, B-cell, and myelocytic and monocytic chimerism were also studied. Peripheral blood cells were analyzed at defined intervals after transplantation from 19 patients with various hematologic malignancies after treatment with myeloablative or nonmyeloablative preparatory regimens. Cell subsets were isolated before analysis of chimerism. Despite the heterogeneity of the patient population and preparatory regimens, all showed rapid and consistent development of DC chimerism. By day +14 after transplantation approximately 80% of DCs were of donor origin with steady increase to more than 95% by day +56. Earlier time points were examined in a subgroup of patients who had undergone nonmyeloablative conditioning and transplantation. These data suggest that a major proportion of blood DCs early after transplantation is donor-derived and that donor chimerism develops rapidly. This information has potential implications for manipulation of immune responses after allogeneic HCT.

scholarly journals Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms

2009 ◽  
Vol 22 (4) ◽  
pp. 651-663 ◽  
Author(s):  
Patricia Price ◽  
David M. Murdoch ◽  
Upasna Agarwal ◽  
Sharon R. Lewin ◽  
Julian H. Elliott ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Granulomatous Inflammation ◽  
T Cell Response ◽  
Immune Restoration ◽  
Immunological Parameters ◽  
Varicella Zoster

SUMMARY Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.

scholarly journals Graft versus self (GvS) against T-cell autoantigens is a mechanism of graft–host interaction

2016 ◽  
Vol 113 (48) ◽  
pp. 13827-13832 ◽  
Author(s):  
Nora Mirza ◽  
Manfred Zierhut ◽  
Andreas Korn ◽  
Antje Bornemann ◽  
Wichard Vogel ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Hematopoietic Cell Transplantation ◽  
Cross Reactivity ◽  
Hematopoietic Cell ◽  
T Cell Epitopes ◽  
Graft Versus Host ◽  
Host Interaction

Graft-versus-host disease (GVHD) represents the major nonrelapse complication of allogeneic hematopoietic cell transplantation. Although rare, the CNS and the eye can be affected. In this study, manifestation in the retina as part of the CNS and T-cell epitopes recognized by the allogeneic T cells were evaluated. In 2 of 6 patients with posttransplantation retina diseases and 6 of 22 patients without ocular symptoms, antigen-specific T-cell responses against retina-specific epitopes were observed. No genetic differences between donor and recipient could be identified indicating T-cell activation against self-antigens (graft versus self). Transplantation of a preexisting immunity and cross-reactivity with ubiquitous epitopes was excluded in family donors and healthy individuals. In summary, an immunological reaction against retina cells represents a mechanism of graft-versus-host interaction following hematopoietic cell transplantation.

Phase 1b study with PEGylated human IL-10 (AM0010) with 5-FU and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 399-399 ◽  
Author(s):  
J. Randolph Hecht ◽  
Aung Naing ◽  
Gerald Falchook ◽  
Manish R. Patel ◽  
Jeffrey R. Infante ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
De Novo ◽  
Single Agent ◽  
Hematological Toxicity ◽  
Phase 1B

399 Background: The benefit of adding nal-irinotecan or oxaliplatin to 5-FU in second-line therapy for PDAC is relatively small and it has been refractory to immune therapies. The success and the durability of immunotherapy is thought to depend on the activation and expansion of intratumoral, tumor specific cytotoxic CD8+ T cells which are absent in most PDACs. AM0010 stimulates the survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Immune stimulation and prolonged stable disease in PDAC patients (pts) with single agent AM0010 was recently presented. Irinotecan may eliminate cytotoxic T cells. Treatment with platinum or 5-FU may activate immune responses to cancer and AM0010 has synergistic anti-tumor function with both in preclinical models. In this phase 1b clinical study, the efficacy of AM0010 with FOLFOX was explored in patients with PDAC. Methods: PDAC pts progressing on a median of 1 prior therapy (range 1-3) were treated daily with AM0010 in combination with FOLFOX (n=20). Tumor responses were monitored using irRC. Immune responses were monitored using analysis of serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Pretreatment samples were analyzed by IHC for tumor infiltration by CD8+ T cells. Results: G3/4 TrAEs included thrombocytopenia (55%), anemia (45%) and neutropenia (25%). There was no significant bleeding or febrile neutropenia. 16 pts had a objective tumor response assessment; 2 had an irCR, 1 an irPR, 10 had irSD. Eight remain on treatment, 2 for > 1 year. ORR was 15%, the DCR was 65%. The mPFS was 3.9 months. AM0010 increased serum Th1 cytokines and reduced mediators of chronic inflammation IL-23 and IL-17 and the immunosuppressive cytokine TGFb. AM0010 increased the number and proliferation of PD1+ activated CD8+ T cells and induced de-novo oligoclonal expansion of T cell clones without affecting total lymphocyte counts. Conclusions: AM0010 with FOLFOX is well tolerated with moderate hematological toxicity in patients with PDAC. The observed immune activation including CD8+ T cell activation and prolonged objective responses are encouraging and will be explored in a phase 3 trial starting in 2016.

Molecular Mechanisms of the AICD Paradoxon in Human T Cells Revealed by an Apototic Role for CD25.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5236-5236
Author(s):  
Guenther Richter ◽  
Karin Hanewinkel ◽  
Andreas Mollweide ◽  
Stefan Burdach
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
Microarray Analysis ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Graft Versus Host Reaction ◽  
Dual Function

Abstract The IL2R is a heterotrimeric receptor consisting of the alpha-chain (CD25) and the two signal transducing beta-, gamma-chains. CD25 monoclonal antibody (e.g. daclizumab) binding to the α-chain, blocks high affinity IL2 binding thereby preventing complete T cell activation. This opportunity to hinder T cell triggering is of ample importance in transplantation medicine and the treatment of autoimmune disease; e.g. for the prevention of an acute graft versus host reaction during allogeneic hematopoietic cell transplantation. However, gene-targeting experiments revealed, that CD25 has an important role in mediating activation induced cell death (AICD) thereby maintaining T cell homeostasis. Thus, CD25 antibodies may not only block T cell activation but may also prevent AICD attributing a dual function to IL2, which has been described by the term AICD paradoxon. The molecular mechanisms of AICD remain to be elucidated. In this study, the modulation of the genomic expression profile of human peripheral blood mononuclear cells (PBMC) with therapeutic concentrations of CD25 mAb was investigated with the aim to identify genes that are involved in T cell activation or in AICD. PBMC were stimulated with OKT3 together with recombinant IL2 in the absence or presence of 30 microgram/ml Daclizumab. Cells were incubated for 16 hrs, RNA extracted and subjected to microarray analysis on U133A gene chips (Affymetrix). Gene chip profile revealed up-regulation of 60 genes and down regulation of 36 genes respectively, by Daclizumab. Anti-CD25 treatment inhibitied cytokine genes typically expressed during T cell activation including CD40L, IL9, TNF-alpha and IFN-gamma as previously shown (e.g. Burdach et al., JCI). Surprisingly, daclizumab also blocked expression of several genes important for susceptibility to apoptosis, such as DR6. In addition, daclizumab reversed IL2-mediated repression of anti-apoptotic genes, such as TOSO. Microarray analysis of these apoptosis related genes was confirmed by RT-PCR and functional assays. In conclusion, CD25-mediated induction of pro-apoptotic as well as repression of anti-apoptotic gene clusters should be considered for future drug development of CD25-antibodies in the clinical arena: these apoptosis related gene products may represent new pharmacologic targets in hematopoietic cell transplantation as well as in the treatment of autoimmune diseases.

scholarly journals Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts

2021 ◽  
Vol 9 (1) ◽  
pp. e001615
Author(s):  
Rachel A Woolaver ◽  
Xiaoguang Wang ◽  
Alexandra L Krinsky ◽  
Brittany C Waschke ◽  
Samantha M Y Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Immune Responses ◽  
Single Cell ◽  
T Cell Activation ◽  
Antitumor Immunity ◽  
Cell Activation ◽  
Tcr Repertoire ◽  
Underlying Mechanisms ◽  
Personalized Cancer

BackgroundAntitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences.MethodsWe developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes.ResultsWe discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRβ sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status.ConclusionsWe reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.

scholarly journals A role for CD9 molecules in T cell activation.

1996 ◽  
Vol 184 (2) ◽  
pp. 753-758 ◽  
Author(s):  
X G Tai ◽  
Y Yashiro ◽  
R Abe ◽  
K Toyooka ◽  
C R Wood ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Expression Cloning ◽  
Wild Type ◽  
Almost All ◽  
Antigen Presenting ◽  
Deficient Mice

Costimulation mediated by the CD28 molecule plays an important role in optimal activation of T cells. However, CD28-deficient mice can mount effective T cell-dependent immune responses, suggesting the existence of other costimulatory systems. In a search for other costimulatory molecules on T cells, we have developed a monoclonal antibody (mAb) that can costimulate T cells in the absence of antigen-presenting cells (APC). The molecule recognized by this mAb, 9D3, was found to be expressed on almost all mature T cells and to be a protein of approximately 24 kD molecular mass. By expression cloning, this molecule was identified as CD9, 9D3 (anti-CD9) synergized with suboptimal doses of anti-CD3 mAb in inducing proliferation by virgin T cells. Costimulation was induced by independent ligation of CD3 and CD9, suggesting that colocalization of these two molecules is not required for T cell activation. The costimulation by anti-CD9 was as potent as that by anti-CD28. Moreover, anti-CD9 costimulated in a CD28-independent way because anti-CD9 equally costimulated T cells from the CD28-deficient as well as wild-type mice. Thus, these results indicate that CD9 serves as a molecule on T cells that can deliver a potent CD28-independent costimulatory signal.

scholarly journals CD5 on dendritic cells regulates CD4+ and CD8+ T cell activation and induction of immune responses

PLoS ONE ◽  
2019 ◽  
Vol 14 (9) ◽  
pp. e0222301 ◽  
Author(s):  
Hui Li ◽  
Erica Burgueño-Bucio ◽  
Shin Xu ◽  
Shaonli Das ◽  
Roxana Olguin-Alor ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell

scholarly journals Murine regulatory T cells differ from conventional T cells in resisting the CTLA-4 reversal of TCR stop-signal

Blood ◽  
2012 ◽  
Vol 120 (23) ◽  
pp. 4560-4570 ◽  
Author(s):  
Yuning Lu ◽  
Helga Schneider ◽  
Christopher E. Rudd
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mechanistic Explanation ◽  
Stop Signal ◽  
Detectable Effect ◽  
First Time

Abstract CTLA-4 inhibits T-cell activation and protects against the development of autoimmunity. We and others previously showed that the coreceptor can induce T-cell motility and shorten dwell times with dendritic cells (DCs). However, it has been unclear whether this property of CTLA-4 affects both conventional T cells (Tconvs) and regulatory T cells (Tregs). Here, we report that CTLA-4 had significantly more potent effects on the motility and contact times of Tconvs than Tregs. This was shown firstly by anti–CTLA-4 reversal of the anti-CD3 stop-signal on FoxP3-negative cells at concentrations that had no effect on FoxP3-positive Tregs. Secondly, the presence of CTLA-4 reduced the contact times of DO11.10 x CD4+CD25− Tconvs, but not DO11.10 x CD4+CD25+ Tregs, with OVA peptide presenting DCs in lymph nodes. Thirdly, blocking of CTLA-4 with anti–CTLA-4 Fab increased the contact times of Tconvs, but not Tregs with DCs. By contrast, the presence of CD28 in a comparison of Cd28−/− and Cd28+/+ DO11.10 T cells had no detectable effect on the contact times of either Tconvs or Tregs with DCs. Our findings identify for the first time a mechanistic explanation to account for CTLA-4–negative regulation of Tconv cells but not Tregs in immune responses.

scholarly journals Vector Order Determines Protection against Pathogenic Simian Immunodeficiency Virus Infection in a Triple-Component Vaccine by Balancing CD4+ and CD8+ T-Cell Responses

2017 ◽  
Vol 91 (23) ◽  
Author(s):  
Ulrike Sauermann ◽  
Antonia Radaelli ◽  
Nicole Stolte-Leeb ◽  
Katharina Raue ◽  
Massimiliano Bissa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Target Cells ◽  
Aids Vaccine ◽  
Cell Responses ◽  
Antibody Titers

ABSTRACT An effective AIDS vaccine should elicit strong humoral and cellular immune responses while maintaining low levels of CD4+ T-cell activation to avoid the generation of target cells for viral infection. The present study investigated two prime-boost regimens, both starting vaccination with single-cycle immunodeficiency virus, followed by two mucosal boosts with either recombinant adenovirus (rAd) or fowlpox virus (rFWPV) expressing SIVmac239 or SIVmac251 gag/pol and env genes, respectively. Finally, vectors were switched and systemically administered to the reciprocal group of animals. Only mucosal rFWPV immunizations followed by systemic rAd boost significantly protected animals against a repeated low-dose intrarectal challenge with pathogenic SIVmac251, resulting in a vaccine efficacy (i.e., risk reduction per exposure) of 68%. Delayed viral acquisition was associated with higher levels of activated CD8+ T cells and Gag-specific gamma interferon (IFN-γ)-secreting CD8+ cells, low virus-specific CD4+ T-cell responses, and low Env antibody titers. In contrast, the systemic rFWPV boost induced strong virus-specific CD4+ T-cell activity. rAd and rFWPV also induced differential patterns of the innate immune responses, thereby possibly shaping the specific immunity. Plasma CXCL10 levels after final immunization correlated directly with virus-specific CD4+ T-cell responses and inversely with the number of exposures to infection. Also, the percentage of activated CD69+ CD8+ T cells correlated with the number of exposures to infection. Differential stimulation of the immune response likely provided the basis for the diverging levels of protection afforded by the vaccine regimen. IMPORTANCE A failed phase II AIDS vaccine trial led to the hypothesis that CD4+ T-cell activation can abrogate any potentially protective effects delivered by vaccination or promote acquisition of the virus because CD4+ T helper cells, required for an effective immune response, also represent the target cells for viral infection. We compared two vaccination protocols that elicited similar levels of Gag-specific immune responses in rhesus macaques. Only the animal group that had a low level of virus-specific CD4+ T cells in combination with high levels of activated CD8+ T cells was significantly protected from infection. Notably, protection was achieved despite the lack of appreciable Env antibody titers. Moreover, we show that both the vector and the route of immunization affected the level of CD4+ T-cell responses. Thus, mucosal immunization with FWPV-based vaccines should be considered a potent prime in prime-boost vaccination protocols.

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