Home About us Contact
|
Home About us Contact | ||
|
|
||
Memory Responses (memory + response)
Selected AbstractsGenerating functional CD8+ T cell memory response under transient CD4+ T cell deficiency: Implications for vaccination of immunocompromised individualsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2008Corey Smith Abstract Studies based on either MHC class II-knockout or CD4+ T cell-depleted murine models have demonstrated a critical role for CD4+ T cells in the generation of CD8+ T cell memory. However, it is difficult to extend these findings to immunocompromised humans where a complete loss of CD4+ T cells is rarely observed. Here, we have developed a model setting, which allows studies on the generation of CD8+ T cell memory responses in a transient CD4+ T cell-deficient setting similar to that seen in immunocompromised patients. Immunisation with an adenoviral vaccine under transient helpless or help-deficient conditions showed varying degrees of impact on the priming of CD8+ T cell responses. Antigen-specific T cells generated under normal CD4+ T cell help and transient help-deficient conditions showed similar effector phenotype and were capable of proliferation upon secondary antigen encounter. Most importantly, in spite of CD4+ T cell deficiency, the long-term CD8+ T cell memory response remained functionally stable and showed comparable cytotoxic effector function as seen in CD8+ T cells generated with normal CD4+ T cell numbers. These findings provide evidence that in spite of partially impaired activation of a primary CD8+ T cell response, a fully functional and stable memory CTL response can be induced under conditions of severe transient CD4+ T cell deficiency. [source] Recovery of Functional Memory T Cells in Lung Transplant Recipients Following Induction Therapy with AlemtuzumabAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2007A. Zeevi Profound T-cell depletion with the monoclonal antibody alemtuzumab facilitates reduced maintenance immunosuppression in abdominal and lung transplantation. While the phenotype of the post-depletional T cells has been characterized, little is known about their function. In the present study, global and CMV-specific T-cell function was assessed longitudinally in 23 lung transplant (LTx) recipients using T-cell assays (ImmuKnow® and T Cell MemoryÔ, Cylex, Columbia, MD) during the first year posttransplant after induction therapy. Recovery of mitogen responses were seen at 2 weeks posttransplantation (65%PHA; 58% Con A), despite the low number of circulating T cells (<2%). These responses declined at 4,5 months (24%PHA; 54% Con A) and were partially reconstituted by 9 months (46% PHA; 73% Con A). CMV-specific responses recovered in 80% of R+ patients as early as 2 weeks posttransplant (n = 5) and 72% of patients had a memory response by 3 months (n = 11). In contrast, only 2 of 5 patients who did not exhibit memory responses pre-transplant (R,) developed transient CMV-specific T-cell responses. Our results show that profound depletion of T cells induced by alemtuzumab spares the functional subset of CMV-specific memory T cells. Conversely, CMV R, patients predepletion may require a prolonged period of prophylaxis. [source] Multiple functions of human T cells generated by experimental malaria challengeEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2009Stephen M. Todryk Abstract Protective immunity generated following malaria infection may be comprised of Ab or T cells against malaria Ag of different stages; however, the short-lived immunity that is observed suggests deficiency in immune memory or regulatory activity. In this study, cellular immune responses were investigated in individuals receiving Plasmodium falciparum sporozoite challenge by the natural (mosquito bite) route as part of a malaria vaccine efficacy trial. Parasitemia, monitored by blood film microscopy and PCR, was subsequently cleared with drugs. All individuals demonstrated stable IFN-,, IL-2 and IL-4 ex vivo ELISPOT effector responses against P. falciparum -infected RBC (iRBC) Ag, 28 and 90,days after challenge. However, infected RBC-specific central memory responses, as measured by IFN-, cultured ELISPOT, were low and unstable over time, despite CD4+ T cells being highly proliferative by CFSE dilution, and showed an inverse relationship to parasite density. In support of the observation of poor memory, co-culture experiments showed reduced responses to common recall Ag, indicating malaria-specific regulatory activity. This activity could not be accounted for by the expression of IL-10, TGF-,, FOXP3 or CTLA-4, but proliferating T cells expressed high levels of CD95, indicating a pro-apoptotic phenotype. Lastly, there was an inverse relationship between FOXP3 expression, when measured 10 days after challenge, and ex vivo IFN-, measured more than 100 days later. This study shows that malaria infection elicits specific Th1 and Th2 effector cells, but concomitant weak central memory and regulatory activity, which may help to explain the short-lived immunity observed. [source] Generating memory with vaccinationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2009Flora Castellino Abstract The goal of vaccination is to induce long-lasting protective immune memory. Although most vaccines induce good memory responses, the type of memory induced by different vaccines may be considerably different. In addition, memory responses to the same vaccine may be influenced by age, environmental and genetic factors. Results emerging from detailed and integrated profiling of immune-responses to natural infection or vaccination suggest that the type and duration of immune memory are largely determined by the magnitude and complexity of innate immune signals that imprint the acquired immune primary responses. Here we summarize results obtained from analyzing human immune memory responses to different types of vaccines. We will also discuss how extending clinical investigation to events occurring early after vaccination can help identify early predictive markers of protective memory and thus contribute to faster development of better and safer vaccines. [source] Generating functional CD8+ T cell memory response under transient CD4+ T cell deficiency: Implications for vaccination of immunocompromised individualsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2008Corey Smith Abstract Studies based on either MHC class II-knockout or CD4+ T cell-depleted murine models have demonstrated a critical role for CD4+ T cells in the generation of CD8+ T cell memory. However, it is difficult to extend these findings to immunocompromised humans where a complete loss of CD4+ T cells is rarely observed. Here, we have developed a model setting, which allows studies on the generation of CD8+ T cell memory responses in a transient CD4+ T cell-deficient setting similar to that seen in immunocompromised patients. Immunisation with an adenoviral vaccine under transient helpless or help-deficient conditions showed varying degrees of impact on the priming of CD8+ T cell responses. Antigen-specific T cells generated under normal CD4+ T cell help and transient help-deficient conditions showed similar effector phenotype and were capable of proliferation upon secondary antigen encounter. Most importantly, in spite of CD4+ T cell deficiency, the long-term CD8+ T cell memory response remained functionally stable and showed comparable cytotoxic effector function as seen in CD8+ T cells generated with normal CD4+ T cell numbers. These findings provide evidence that in spite of partially impaired activation of a primary CD8+ T cell response, a fully functional and stable memory CTL response can be induced under conditions of severe transient CD4+ T cell deficiency. [source] The key regulators of adult T helper cell responses, STAT6 and T-bet, are established in early life in miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2006Shawn Rose Abstract Murine neonatal immunity is typically Th2 biased. This is characterized by high-level IL-4 production at all phases of the immune response and poor IFN-, memory responses. The differential expression of Th1/Th2 cytokines by neonates and adults could arise if the critical regulators of Th differentiation and function, STAT6 and T-bet, operate differently during the neonatal period. To test this idea, the Th cell responses of wild-type, T-bet-deficient, or STAT6-deficient mice were compared in vitro and in vivo. The absence of these factors had similar qualitative effects on the development of effector function in neonates and adults, i.e., if a Th lineage was inhibited or enhanced in adult animals, a similar phenomenon was observed in neonates. However, there was a striking difference observed in the in vivo Th1 memory responses of STAT6-deficient mice initially immunized as neonates. Antigen-specific IFN-, production was increased 50,100-fold in STAT6-deficient neonates, achieving levels similar to those of STAT6-deficient adults. These findings demonstrate that STAT6 and T-bet signals are central in shaping Th responses in wild-type neonates, as in adult mice, and that the master regulators of Th cell development and function are already firmly established in early life. [source] Incomplete effector/memory differentiation of antigen-primed CD8+ T,cells in gene gun DNA-vaccinated miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2003Christina Bartholdy Abstract DNA vaccination is an efficient way to induce CD8+ T,cell memory, but it is still unclear to what extent such memory responses afford protection in vivo. To study this, we induced CD8+ memory responses directed towards defined viral epitopes, using DNA vaccines encoding immunodominant MHC class,I-restricted epitopes of lymphocytic choriomeningitis virus covalently linked to ,2-microglobulin. This vaccine construct primed for a stronger recall response than did a more conventional minigene construct. Despite this, vaccinated mice were only protected against systemic infection whereas protection against the consequences of peripheral challenge was limited. Phenotypic analysis revealed that DNA vaccine-primed CD8+ T,cells in uninfected mice differed from virus-primed CD8+ T,cells particularly regarding expression of very-late antigen (VLA)-4, an adhesion molecule important for targeting T,cells to inflammatory sites. Thus, our DNA vaccine induces a long-lived memory CD8+ T,cell population that provides efficient protection against high-dose systemic infection. However, viral replication in solid non-lymphoid organs is not curtailed sufficiently fast to prevent significant virus-induced inflammation. Our results suggest that this is due to qualitative limitations of the primed CD8+ T,cells. [source] Differential CD4+ T-cell memory responses induced by two subsets of human monocyte-derived dendritic cellsIMMUNOLOGY, Issue 3 2007Sandra Bajaña Summary Dendritic cells (DC) are powerful inducers of primary T-cell responses, but their role in secondary responses has not been extensively analysed. Here, we address the role of two DC subsets derived from human CD16+ (16+ mDC) or CD16, (16, mDC) monocytes on the reactivation of memory responses. CD4+ CD45RA, memory T cells were obtained from adult blood donors, and central (TCM) and effector (TEM) memory T cells were isolated by fluorescence-activated cell sorting with anti-CCR7 antibodies. The 16+ mDC and 16, mDC were cocultured with autologous lymphocytes, either unpulsed or loaded with purified protein derivatives of Mycobacterium tuberculosis (PPD) or tetanus toxoid (TT), and were analysed for up to 8 days. Over a range of doses, 16+ mDC drove stronger T-cell proliferative responses against both antigens. Overall, antigen-specific memory cells tended to acquire a phenotype of TEM at later time-points in the culture, whereas cells that had completed fewer cycles of division were similar to TCM. The 16+ mDC induced higher rates of proliferation on both TCM and TEM lymphocytes than 16, mDC. This phenomenon was not related to the ability of both DC to induce CD25 expression on T cells, to lower secretion of interleukin-2, or to raise production of interleukin-10 during T-cell/16, mDC cocultures. The induction of TCM effector capacity in terms of interferon-, production was faster and more pronounced with 16+ mDC, whereas both DC had similar abilities with TEM. In conclusion, these data might reveal new potentials in vaccination protocols with 16+ mDC aimed at inducing strong responses on central memory T cells. [source] IgE-mediated facilitated antigen presentation underlies higher immune responses in peanut allergyALLERGY, Issue 10 2010V. Turcanu To cite this article: Turcanu V, Stephens AC, Chan SMH, Rancé F, Lack G. IgE-mediated facilitated antigen presentation underlies higher immune responses in peanut allergy. Allergy 2010; 65: 1274,1281. Abstract Background:, Peanut allergy poses significant healthcare problems, because its prevalence is increasing in many countries, and it is rarely outgrown. To explore the immunological mechanisms that underlie peanut allergy and tolerance, we compared the peanut-specific responses of peanut-allergic (PA) and nonallergic (NA) individuals. Methods:, We measured peanut-specific peripheral blood mononuclear cells (PBMC) proliferation using tritiated thymidine. The frequency of peanut-specific T cells amongst PBMC was determined by carboxyfluorescein succinimidyl ester labelling. The role of IgE-dependent facilitated antigen presentation (FAP) in modulating proliferation was investigated by depleting IgE from plasma with anti-IgE-coated beads and then assessing PBMC proliferation in the presence of IgE-depleted or nondepleted plasma. Results:, We found that peanut-specific PBMC proliferation is higher and peaks earlier in PA than in NA donors. We investigated the immunological mechanisms that could underlie these differences. We found that both PA and NA have memory responses to peanut, but the frequency of peanut-specific T cells is higher in PA than in NA. Facilitated antigen presentation could cause both the higher proliferation and precursor frequency in PA. Facilitated antigen presentation activity in vitro was confirmed by showing that IgE depletion decreases proliferation, while adding IgE back restores it. Conclusion:, Our results identify FAP as a mechanism that underlies higher responses to peanut in PA. In these individuals, high levels of peanut-specific IgE could furthermore maintain long-term allergic T-cell responses. We raise the question whether, in the future, therapies targeting IgE such as anti-IgE antibodies may be used to suppress these T-cell responses. [source] Aging Augments IL-17 T-Cell Alloimmune ResponsesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009B. M. Tesar As increasing numbers of elderly patients require solid organ transplantation, the need to better understand how aging modifies alloimmune responses increases. Here, we examined whether aged mice exhibit augmented, donor-specific memory responses prior to transplantation. We found that elevated donor-specific IL-17, but not IFN-,, responses were observed in aged mice compared to young mice prior to transplantation. Further characterization of the heightened IL-17 alloimmune response with aging demonstrated that memory CD4+ T cells were required. Reduced IL-2 alloimmune responses with age contributed to the elevated IL-17 phenotype in vitro, and treatment with an anti-IL-17 antibody delayed the onset of acute allograft rejection. In conclusion, aging leads to augmented, donor-specific IL-17 immune responses that are important for the timing of acute allograft rejection in aged recipients. IL-17 targeting therapies may be useful for averting transplant rejection responses in older transplant recipients. [source] Cord blood memory responses: are we being naïve?CLINICAL & EXPERIMENTAL ALLERGY, Issue 11 2001S. L. Prescott First page of article [source] High-affinity human leucocyte antigen class I binding variola-derived peptides induce CD4+ T cell responses more than 30 years post-vaccinia virus vaccinationCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2009M. Wang Summary Interferon-, secreting T lymphocytes against pox virus-derived synthetic 9-mer peptides were tested by enzyme-linked immunospot in peripheral blood of individuals vaccinated with vaccinia virus more than 30 years ago. The peptides were characterized biochemically as high-affinity human leucocyte antigen (HLA) class I binders (KD , 5 nM). However, five of the individuals tested did not show typical CD8+ T cell-mediated HLA class I-restricted responses. Instead, these donors showed CD4+ T cell-dependent responses against four of a total of eight antigenic 9-mer peptides discovered recently by our group. These latter responses were blocked specifically in the presence of anti-HLA class II antibody. We conclude that long-lived memory responses against pox virus-derived 9-mer peptides, with high binding affinity for HLA class I molecules, are mediated in some cases by CD4+ T cells and apparently restricted by HLA class II molecules. [source] | ||||||||||||||||||||||