Humoral and T-cell immune response after three doses of mRNA SARS-CoV-2 vaccines in fragile patients: the Italian VAX4FRAIL study

Background: Patients with solid or hematological tumors, neurological and immune-inflammatory disorders represent potentially fragile subjects with increased risk to experience severe COVID-19 and inadequate response to SARS-CoV2 vaccination. Methods: We designed a prospective Italian multicentric study to assess humoral and T-cell response to SARS-CoV2 vaccination in patients (n=378) with solid tumors (ST), hematological malignancies (HM), neurological (ND) and immuno-rheumatological diseases (ID). The immunogenicity of primary vaccination schedule and of the booster dose were analyzed. Results: Overall, patient seroconversion rate after two doses was 62.1%. A significant lower rate was observed in HM (52.4%) and ID (51.9%) patients compared to ST (95.6%) and ND (70.7%); a lower median level of antibodies was detected in HM and ID versus the others (p<0.0001). A similar rate of patients with a positive SARS-CoV2 T-cell response was observed in all disease groups, with a higher level observed in the ND group. The booster dose improved humoral responses in all disease groups, although with a lower response in HM patients, while the T-cell response increased similarly in all groups. In the multivariable logistic model, the independent predictors for seroconversion were disease subgroups, type of therapies and age. Notably, the ongoing treatment known to affect the immune system was associated with the worst humoral response to vaccination (p<0.0001), but had no effects on the T-cell responses. Conclusions: Immunosuppressive treatment more than disease type per se is a risk factor for low humoral response after vaccination. The booster dose can improve both humoral and T-cell response.

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Nano-Microparticle Platforms in Developing Next-Generation Vaccines

Vaccines ◽

10.3390/vaccines9060606 ◽

2021 ◽

Vol 9 (6) ◽

pp. 606

Author(s):

Giuseppe Cappellano ◽

Hugo Abreu ◽

Chiara Casale ◽

Umberto Dianzani ◽

Annalisa Chiocchetti

Keyword(s):

Immune Response ◽

T Cell ◽

Cell Response ◽

Humoral Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Next Generation ◽

Emerging Viruses ◽

Whole Cells ◽

Effector Functions

The first vaccines ever made were based on live-attenuated or inactivated pathogens, either whole cells or fragments. Although these vaccines required the co-administration of antigens with adjuvants to induce a strong humoral response, they could only elicit a poor CD8+ T-cell response. In contrast, next-generation nano/microparticle-based vaccines offer several advantages over traditional ones because they can induce a more potent CD8+ T-cell response and, at the same time, are ideal carriers for proteins, adjuvants, and nucleic acids. The fact that these nanocarriers can be loaded with molecules able to modulate the immune response by inducing different effector functions and regulatory activities makes them ideal tools for inverse vaccination, whose goal is to shut down the immune response in autoimmune diseases. Poly (lactic-co-glycolic acid) (PLGA) and liposomes are biocompatible materials approved by the Food and Drug Administration (FDA) for clinical use and are, therefore, suitable for nanoparticle-based vaccines. Recently, another candidate platform for innovative vaccines based on extracellular vesicles (EVs) has been shown to efficiently co-deliver antigens and adjuvants. This review will discuss the potential use of PLGA-NPs, liposomes, and EVs as carriers of peptides, adjuvants, mRNA, and DNA for the development of next-generation vaccines against endemic and emerging viruses in light of the recent COVID-19 pandemic.

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Recovery of CMV-Specific T Cells Following Alternative Donor Allogeneic Transplant with Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood.v126.23.5462.5462 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5462-5462

Author(s):

Ayman Saad ◽

Samantha B Langford ◽

Shin Mineishi ◽

Lawrence S. Lamb

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Cell Recovery ◽

Post Transplant ◽

Increased Risk ◽

Cmv Reactivation

Abstract Background: Post-transplant cyclophosphamide (PTCy) is increasingly used for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation (HCT) using alternative donors. However, immune reconstitution can be delayed posing an increased risk for CMV reactivation. We evaluated the outcomes of patients who received HCT-apheresis products comparing the impact of PTCy on lymphocyte recovery, CMV reactivation and CMV-specific CD8+ T cell recovery following haplo-identical (HAPLO), matched unrelated donor (MUD), and mismatched unrelated donor (mMUD) grafts vs. with conventional matched related donor (MRD) graft recipients. Methods: We examined 26 patients (median age, 49 years; range, 20-72 years) with advanced hematologic malignancies; n=5 (HAPLO); 6 (MRD); 15 (MUD). All patients received myeloablative conditioning regimens that was either busulfan- or total body irradiation (TBI)-based. PTCy (50 mg/kg/day) was administered on days +3 and +4 following HAPLO and on day +3 following MUD/mMUD transplant. Peripheral blood lymphocyte reconstitution and frequency of circulating CMV-directed CD8+ T cells was assessed (day ± 10 days) on post-transplant days +30, +60, and +90. Circulating anti-CMV T cell frequency was assessed using a phycoerythrin-tagged MHC dextramer against HLA-specific CMV pp65, IE-1, or pp50 peptides (Immudex; Copenhagen, DK) in combination with Tru-Count¨ tubes and fluorescent-labeled monoclonal antibodies against CD3, CD8, CD4, CD16/56, and CD19 (BD Biosciences; San Jose, CA). Anti-CMV CD8+ T cell immunity was defined as a CMV-dextramer (CMV/DEX) positive count of ≥7cells/ml. CMV reactivation was defined as a serologic titer of >500IU/mL. All patients with CMV reactivation received ganciclovir therapy until CMV titer became negative. Results: Day +30 total T cell recovery was significantly faster in MRD than CY-treated recipients (p=0.015) due principally to more robust CD8+ T cell recovery. CD4 T cell recovery remained below normal range in all groups through day +100. NK cells recovered to normal numbers at day +28 in all groups. Neither PTCy nor donor source significantly impacted the percentage of patients that recovered anti-CMV CD8+ T cells at each time interval (p = 0.8232). Excluding donors (D) and recipients (R) that were both negative, CMV/DEX+ T cells recovery was >7/mL in 4/5 MRD, 7/14 MUD, and 3/5 HAPLO by day +100. Among MRD recipients either D+ or R+ (n=5), 2 patients showed CMV reactivation within 40 days of transplant that was associated with <7 CMV/DEX+ T cells on day +30. Subsequent high (>90/mL) CMV/DEX T cell response in one patient shortened the duration of viremia to 10 days (vs. 16 days with poor responder) and 3 patients showed no CMV reactivation and a high CMV/DEX+ T cell response by day +60. For MUD CMV D+ and/or R+ recipients (n=14), 3 showed CMV reactivation within 50 days of transplant. All 3 patients had suboptimal CMV/DEX T cell response on day +30. Robust CMV/DEX+ T cell response on day +60 predicted shorter duration of viremia (20 days vs. average of 32 days). For HAPLO CMV D+ and/or R+ (n=5) recipients, 4 experienced CMV reactivation within 50 days of transplant. All patients had a <7 CMV/DEX+ T cells/mL +30. Robust CMV/DEX+ T cell response by day +60 was associated with shorter duration of viremia (range 7-21 days), while one patient with <7/mL CMV/DEX+ T cells had continued CMV viremia for 36 days. Conclusion: In this preliminary analysis, neither PTCy nor donor source significantly impacted the percentage of patients that recovered anti-CMV CD8+ T cells at each time interval. A weak CMV/DEX+ response (<7 cells/mL) on day +30 was consistent with increased risk of CMV reactivation (viremia) in all groups. A CMV/DEX+ T cell count ≥7 cells/mL was not immediately protective against CMV reactivation, but higher counts were associated with a shortened duration of viremia while on antiviral therapy. Conversely, subnormal counts were associated with a longer duration of viremia. This interim analysis suggests that CMV/DEX+ T cell enumeration is a useful biologic correlate for determining clinical response to antiviral therapy, and that donor-derived CMV specific T cell immunity is not further compromised with following PTCy in alternative donor HCT. Disclosures No relevant conflicts of interest to declare.

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Cellular and humoral immunogenicity of the mRNA-1273 SARS-CoV-2 vaccine in patients with hematologic malignancies

Blood Advances ◽

10.1182/bloodadvances.2021006101 ◽

2021 ◽

Author(s):

Moraima Jiménez ◽

Elisa Roldan ◽

Candela Fernández- Naval ◽

Guillermo Villacampa ◽

Monica Martinez-Gallo ◽

...

Keyword(s):

T Cell ◽

Cellular Response ◽

Immunosuppressive Agents ◽

Immunosuppressive Treatment ◽

Humoral Response ◽

Hematologic Malignancies ◽

T Cell Response ◽

Cell Counts ◽

Immuno Assay ◽

Anti Cd20

Recent studies have demonstrated a suboptimal humoral response to SARS-CoV-2 mRNA vaccines in patients diagnosed with hematologic malignancies, however data about cellular immunogenicity is scarce. In this study we aimed to evaluate both the humoral and cellular immunogenicity one month after the second dose of the mRNA-1273 vaccine. Antibody titers were measured by the Elecsys and LIAISON Anti-SARS-CoV-2 S assay while T-cell response was assessed by Interferon-Gamma-Release-immuno-Assay technology. Overall, 76.3% (184/241) of patients developed humoral immunity and the cellular response rate was 79% (184/233). Hypogammaglobulinemia, lymphopenia, active hematological treatment and anti-CD20 therapy during the last 6 months were associated with an inferior humoral response. Conversely, age over 65 years, active disease, lymphopenia and immunosuppressive treatment for GvHD were associated with an impaired cellular response. A significant dissociation between humoral and cellular response was observed in patients treated with anti-CD20 therapy, being the humoral response of 17.5% whereas the cellular response was 71.1%. In these patients B-cell aplasia was confirmed while T cell counts were preserved. In contrast, humoral response was observed in 77.3% of patients under immunosuppressive treatment for GvHD, while only 52.4% had cellular response. The cellular and humoral response to the SARS-CoV-2 mRNA-1273 vaccine in patients with hematological malignancies is highly influenced by the presence of treatments like anti-CD20 therapy and immunosuppressive agents. This observation has implications for the further management of these patients.

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Sars-Cov-2 T-Cell Response in Allogeneic Hematopoietic Stem Cell Recipients Following Two Doses of BNT162b2 Vaccine

Blood ◽

10.1182/blood-2021-149139 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2895-2895

Author(s):

Beatrice Clemenceau ◽

Thierry Guillaume ◽

Marianne Coste-Burel ◽

Pierre Peterlin ◽

Alice Garnier ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

Cellular Immunity ◽

Cell Response ◽

Humoral Response ◽

T Cell Response ◽

Healthy Controls ◽

Hematopoietic Stem ◽

Hla Dr

Abstract Introduction: Virus-specific humoral and cellular immune responses act synergistically to protect from viral infection. In our recent observational monocentric study of 117 hematopoietic stem cell adult recipients, we found that 54% and 83 % patients achieved a humoral response after two doses of BNT162b2 anti-SARS-CoV-2 messenger RNA vaccine (Pfizer BioNTech), respectively. Here, we evaluated the T-cell response against the SARS-Cov-2 spike protein after two doses of BNT162b2 vaccine in some allografted patients from the same cohort and compared these results to those from healthy controls. Methods: To quantify SARS-CoV-2 specific T-cells, we used an INFg ELISpot assay that detects these cells after activation of peripheral blood mononuclear cells (PBMC) with 3 peptide pools covering the whole protein sequence of the spike glycoprotein (Prot _S1; _S+ and _S PepTivator peptide pools, Miltenyi Biotec, Bergisch Gladbach, Germany). EBV and CMV specific T-cells were also quantified as controls. The immunophenotype of PBMC was determined by flow cytometry, after dead cell exclusion, with monoclonal antibodies identifying the following surface antigens: CD45, CD3, CD14, CD19 and HLA-DR. The frequencies of spot-forming units (SFU) were reported as per 10 6 CD3+ T-cells. Results: Samples from 46 allografted patients (acute myeloblastic leukemia, N=27, myelodysplastic syndrome, N=19) and 16 healthy controls were available. Characteristics of the population are given in Table 1. All fully vaccinated healthy donors became seropositive and developed a positive T-cell response to spike peptide pools even though variable frequencies were observed. The median response was 195 SFU/10 6 T-cells. By comparison, the frequency of EBV-specific T-cells was 774 SFU/10 6 T-cells (Figure 1). In the group of patients, 78% (n=36/46) had achieved a humoral response after the second dose of vaccine. Among these humoral responders (HR), 89% (n=32/36) also had a positive anti-spike T-cell response with variable frequencies (median =119 SFU/10 6 T-cells. For 8 patients, this T cell response was higher than that of controls (>800 SFU/10 6 T-cells) (Figure 1), which is equivalent to more than 1 specific T-cell per microliter of blood (Figure 2). The humoral responders (HR) who did not develop a T-cell response (11%, n=4/36) had a median time from transplant to vaccination of 523 days compared to 1032 days for cellular responder patients. Among the 10 patients who were non humoral responders (NHR) (22%, n=10/46), 4 (40%) developed a cellular immunity, including one with a very high T cell response (1333 SFU/10 6 T-cells). As expected, the absence of humoral response was observed in patients who were within one year of the transplant. Of note, somehow unexpectedly, patients often presented a high frequency of EBV- and CMV-specific T cells (Figures 1 & 2). As expected, PBMC immunophenotypic analysis revealed that CD3+ frequencies were lower in patients compared to those of controls but were similar between HR and NHR. NHR had very low frequencies of B cells and interestingly, they had an elevated frequency of CD14+ monocytes with low/neg HLA-DR expression potentially corresponding to myeloid-derived suppressor cells (MDSCs) (Figure 3). Conclusion: In this series, 89% of allografted patients who developed an anti-spike humoral response also presented an anti-SARS-Cov-2 cellular immunity. Interestingly, anti-SARS-Cov-2 specific T-cells could be detected in 40% of NHR patients. Although a larger group of patients is required to confirm these results, it remains to be determined whether this T-cell response is protective against SARS-Cov-2 infection as previously demonstrated for CMV (Litjens et al, 2017). Finally, the role of potential immunosuppressive MDSCs must be explored in patients who develop no sign of T-cell response after vaccination. Figure 1 Figure 1. Disclosures Moreau: Oncopeptides: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Amgen: Honoraria.

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Cellular Immune Responses to BNT162b2 mRNA COVID-19 Vaccine in Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2021-150796 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 638-638

Author(s):

Gilad Itchaki ◽

Lior Rokach ◽

Ohad Benjamini ◽

Osnat Bairey ◽

Adi Sabag ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Cell Response ◽

Research Funding ◽

T Cell Response ◽

Lymphocytic Leukemia ◽

Cell Immune Response ◽

P Value ◽

Igg Antibodies ◽

Cellular Immune

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) are known to have a suboptimal immune response of both humoral and cellular arms. Recently, a BNT162b2 mRNA COVID-19 vaccine was introduced with a high efficacy of 95% in immunocompetent individuals. Approximately half of the patients with CLL fail to mount a humoral response to the vaccine, as detected by anti-spike antibodies. Currently, there is no data available regarding T-cell immune responses following the vaccine of these patients. Aim of the study: To investigate T-cell response determined by interferon gamma (IFNγ) secretion in patients with CLL following BNT162b mRNA Covid-19 vaccine, in comparison with serologic response. Methods: CLL patients from 3 medical centers in Israel were included in the study. All patients received two 30-μg doses of BNT162b2 vaccine (Pfizer), administered intramuscularly 3 weeks apart. For evaluation of SARS-CoV-2 Spike-specific T-cell responses, blood samples were stimulated ex-vivo with Spike protein and secreted IFNγ was quantified (ELISA DuoSet, R&D Systems, Minneapolis, Minnesota, USA). T-cell immune response was considered to be positive for values above 25 pg/ml of Spike-specific response. T-cell subpopulations were characterized by flow cytometry (CD3, CD4, CD8). Anti-spike antibody tests were performed using the Architect AdviseDx SARS-CoV-2 IgG II (Abbot, Lake Forest, Illinois, USA). Statistical analysis was performed using Mann-Whitney test for continuous variables while the Wald Chi-square test was used for comparing categorical variables. Results: 83 patients with CLL were tested for T-cell response. Blood samples were collected after a median time of 139 days post administration of the second dose of vaccine (IQ range 134-152). Out of 83 patients, 68 were eligible for the analysis (with positive internal control). Median age of the cohort was 68 years (56-72); and 44 (65%) were males. 19 (28%) patients were treatment-naïve, most of whom were Binet stage A or B. 31 (46%) patients were on therapy: 17 with a BTK-inhibitor, and 13 with a venetoclax-based regimen. 29 (42%) patients were previously treated with anti-CD20, 13 of whom in the 12 months period prior to vaccination. T cell immune response to the vaccine was evident in 22 (32%) patients. CIRS Score>6 and specifically hypertension were statistically significantly associated with a lower T-cell response (univariate analysis, p-value<0.05). Variables that were associated with the development of T-cell response were presence of del(13q), IgM ≥ 40 mg/dL, and IgA ≥ 80 mg/dL (p-value 0.05-0.1). There was no significant difference with regards to age, gender, other CLL-specific prognostic markers, treatment, and T-cell subpopulation distribution according to flow cytometry (Table 1). The presence of T-cell response highly correlated with both the detection of anti-spike IgG antibodies following the second dose (p=0.0239) and at the time of T-cell testing (n=66, p=0.048, Table 2). While 50% of patients who tested positive for anti-spike IgG antibodies also developed positive T-cell response, only 17% of patients who did not develop T-cell response, tested positive for anti-spike antibodies. Importantly, 24% of the patients who tested negative for anti-spike IgG antibodies, developed positive T cell response. Moreover, the level of the T-cell response (log transformed) correlated linearly with (log transformed) anti-spike IgG titer (adjusted r=0.26 and p =0.026 according to Pearson correlation, Figure 1). Conclusion: We show that cellular immune response to the BNT162b2 mRNA COVID-19 vaccine, is blunted in most CLL patients and that there is a correlation between T-cell response and serologic response to the vaccine. These results need to be validated in a larger cohort. Figure 1 Figure 1. Disclosures Itchaki: AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Benjamini: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tadmor: AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

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The Cytomegalovirus-Specific CD4+ T-Cell Response Expands with Age and Markedly Alters the CD4+ T-Cell Repertoire

Journal of Virology ◽

10.1128/jvi.01262-06 ◽

2007 ◽

Vol 81 (14) ◽

pp. 7759-7765 ◽

Cited By ~ 139

Author(s):

Batoul Pourgheysari ◽

Naeem Khan ◽

Donna Best ◽

Rachel Bruton ◽

Laxman Nayak ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

Cd4 T Cell ◽

Cell Immune Response ◽

T Cell Repertoire ◽

Immune Senescence ◽

Cell Repertoire

ABSTRACT Immune function in the elderly is associated with a number of phenotypic and functional abnormalities, and this phenomenon of immune senescence is associated with increased susceptibility to infection. The immune response to pathogens frequently declines with age, but the CD8+ T-cell response to cytomegalovirus (CMV) is unusual, as it demonstrates a significant expansion over time. Here we have documented the CD4+ T-cell immune response to CMV in healthy donors of different ages. The magnitude of the CMV-specific CD4+ T-cell immune response increases from a mean of 2.2% of the CD4+ T-cell pool in donors below 50 years of age to 4.7% in donors aged over 65 years. In addition, CMV-specific CD4+ T cells in elderly donors demonstrate decreased production of interleukin-2 and less dependence on costimulation. CMV seropositivity is associated with marked changes in the phenotype of the overall CD4+ T-cell repertoire in healthy aged donors, including an increase in CD57+ expression and a decrease in CD28 and CD27 expression, a phenotypic profile characteristic of immune senescence. This memory inflation of CMV-specific CD4+ T cells contributes to evidence that CMV infection may be damaging to immune function in elderly individuals.

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Transient but Reversible Activation Defect of T-Cell Responses Against Cytomegalovirus and Adenovirus through Immunosuppresion with Calcineurin Inhibitors.

Blood ◽

10.1182/blood.v116.21.4542.4542 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4542-4542

Author(s):

Cornelia Neinhaus ◽

Kathrin Opherk ◽

Simone Kayser ◽

Joseph Leibold ◽

Judith Feucht ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Response ◽

Cell Activation ◽

Immunosuppressive Treatment ◽

Calcineurin Inhibitors ◽

T Cell Response ◽

T Cell Proliferation ◽

Ciclosporin A

Abstract Abstract 4542 Immunosuppressive treatment is widely used, especially after allogeneic stem cell transplantation (HSCT) to prevent or treat graft versus host disease (GvHD). Common drugs are Ciclosporin A or Tacrolimus in combination with steroids. However, immunosuppressive treatment and the underlying conditions are associated with an increased risk of viral reactivations with persistent pathogens like cytomegalovirus or adenovirus. In the absence of a protective immune response, virus infection remains a life-threatening complication after HSCT. Here we investigated the antiviral T-cell response (n=12) after ex vivo exposition with Ciclosporin A, Tacrolimus, Prednisolone or Mycophenolate at time of immunosuppression, 24 hours and 72 hours later. Analysis has been done with IFNgamma Elispot assays, confirmed by intracellular cytokine staining in flow cytometry and analysis of T-cell proliferation detected by CFSE. The antiviral T-cell response is suppressed after 24 hours using normal serum concentrations (100-200ng/ml) of cyclosporine A. T-cell annergy, induced by cyclosporine, could be reversible, after 72 without immunosuppression. Tacrolimus has a stronger immunosuppressive effect on T-cell activation within the same time and even low levels of 1ng/ml induce T-cell suppression after 72 hours. Peak levels of calcineurin inhibitors even suppressed the T-cell response to superantigens like staphylococcal antigen B or PHA. As expected, Prednisolone had a short and dose dependend effect on T-cell activation. Mycophenolate has a mild effect on the activation of virus-specific T-cells. However, all three drugs induced a significant reduction in Ag-specific T-cell proliferation. In conclusion, Interferonγ detection in virus-specific T-cells is a good diagnostic tool for clinicians to monitor the risk of viral complications in immunosuppressed patients. Tacrolimus, Cyclosporin A, Prednisolone and Mycophenolate induce an activation defect in Ag-specific T-cells with decreasing severity. The effect is reversible and corresponds to high or low serum levels. Disclosures: No relevant conflicts of interest to declare.

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Abstract 486: Chronic Periodontitis Induces Adverse Post-myocardial Wound Healing Through Activation of CD8+ T-cells

Circulation Research ◽

10.1161/res.127.suppl_1.486 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Yusra Zaidi ◽

Miguel Troncoso ◽

Daria Ilatovskaya ◽

Kristine Y Deleon-pennell

Keyword(s):

T Cells ◽

T Cell ◽

Ligand Binding ◽

Cd8 T Cells ◽

Cardiac Remodeling ◽

Chronic Periodontitis ◽

Cell Response ◽

T Cell Response ◽

Memory Cd8 T Cells ◽

Increased Risk

Increased risk of adverse cardiac remodeling post-myocardial infarction (MI) has been observed in patients with periodontal disease. Previously, we demonstrated that chronic inflammation induced by periodontal pathogen Porphyromonas gingivalis lipopolysaccharide (LPS) resets cardiac homeostasis, causing acceleration and exacerbation of the macrophage response post-MI. We hypothesize that chronic LPS activates a memory T-cell response resulting in adverse cardiac remodeling post-MI. Analysis of the mouse heart attack research tool (mHART) 1.0 identified 135 mice (5.4 ± 0.1 months of age) associated with the LPS study that had both echo and plasma data collected. Of these 26 mice also had tissue blocks in the mHART tissue bank. Mice were grouped as follows: 1) Saline day 0 unoperated mice (D0), 2) 28 day LPS day 0 unoperated mice (LPS), 3) Saline day 1 MI (MI), and 4) 28 day LPS day 1 MI (LPS+MI). Immunofluorescence of the left ventricle (LV) demonstrated that chronic LPS increased the number of memory CD8+ T-cells (CD3+CD8+CD27+) in the LV and remained elevated in the LPS+MI group compared to D0 and MI controls. Similar to chronic LPS, ligature-induced periodontitis (21 days) also showed upregulation of CD8+ T-cells in the LV along with changes in plasma proteins associated with interleukin, cytokine, chemokine receptor binding, peptide ligand-binding, inflammasome pathway, class A/1 rhodopsin-like receptors, G-protein coupled receptor ligand binding, and RUNX1 and FOXP3 control of Treg development and signaling. To dissect T-cell mediated signaling pathways, we constantly infused an MHC-I blocking antibody (MHCi; 0.2 μg/day; n=3) by osmotic mini-pumps implanted subcutaneously 7 days before (21 days after LPS infusion) and after MI surgery. Interestingly, MHCi attenuated the effector CD8+ T-cell response (CD3+CD8+CD44+) without affecting the memory response. MHCi also attenuated macrophage numbers within the infarct, thereby improving cardiac function at post-MI day 1. Our data showed the recruitment of effector but not memory CD8+ T-cells is regulating macrophage-mediated adverse post-MI remodeling in the setting of chronic periodontitis.

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Lack of Interleukin-12 in p40-Deficient Mice Leads to Poor CD8+ T-Cell Immunity against Encephalitozoon cuniculi Infection

Infection and Immunity ◽

10.1128/iai.00753-09 ◽

2010 ◽

Vol 78 (6) ◽

pp. 2505-2511 ◽

Cited By ~ 17

Author(s):

Magali M. Moretto ◽

Elizabeth M. Lawlor ◽

Imtiaz A. Khan

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

Scid Mice ◽

T Cell Immunity ◽

Interleukin 12 ◽

Cell Immune Response ◽

Encephalitozoon Cuniculi ◽

Cell Immunity

ABSTRACT A CD8+ T-cell response is critical for protection against Encephalitozoon cuniculi infection. However, the factors responsible for the generation of CD8+ T-cell immunity during E. cuniculi infection and the cytokines involved in this process have not been identified. In the present study, we demonstrated that p40-deficient animals, which are unable to produce interleukin-12 (IL-12), have a serious defect in expansion of the CD8+ T-cell response which compromises the survival of an infected host. Adoptive transfer of CD8+ T cells from immunocompetent donors protected SCID mice infected with E. cuniculi, whereas administration of CD8+ T cells from p40−/− mice failed to protect infected SCID mice. In vitro dendritic cell (DC) cultures from knockout mice pulsed with E. cuniculi spores were unable to develop a robust CD8+ T-cell immune response. Addition of exogenous IL-12 or transfer of CD8+ T cells that were initially primed with DC from p40−/− animals to DC cultures from immunocompetent mice (directly or via transwells) led to optimal expansion of these cells. This IL-12-mediated reinstatement of CD8+ T-effector immunity was independent of gamma interferon (IFN-γ) as addition of antibody to the cultures failed to have an effect. These studies demonstrated that IL-12 plays a predominant role in the expansion of effector CD8+ T-cell immunity against E. cuniculi, which is critical for host survival. These findings are very important for understanding the protective immune mechanisms needed to protect an immunocompromised host against an opportunistic infection and can be extended to other microsporidial pathogens.

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Epidemiology and Clinical Features of Cryptosporidium Infection in Immunocompromised Patients

Clinical Microbiology Reviews ◽

10.1128/cmr.15.1.145-154.2002 ◽

2002 ◽

Vol 15 (1) ◽

pp. 145-154 ◽

Cited By ~ 289

Author(s):

Paul R. Hunter ◽

Gordon Nichols

Keyword(s):

T Cell ◽

Cell Response ◽

Diarrheal Disease ◽

Gastrointestinal Disease ◽

Severe Disease ◽

Severe Combined Immunodeficiency ◽

The United States ◽

T Cell Response ◽

Increased Risk ◽

Immunodeficiency Syndrome

SUMMARY Cryptosporidium spp. are a major cause of diarrheal disease in both immunocompetent and immunodeficient individuals. They also cause waterborne disease in both the United States and United Kingdom. Studies on the mechanisms of immunity to cryptosporidiosis indicate the importance of the T-cell response. The spectrum and severity of disease in immunocompromised individuals with cryptosporidiosis reflect this importance since the most severe disease is seen in individuals with defects in the T-cell response. The most commonly studied group is that of patients with AIDS. These patients suffer from more severe and prolonged gastrointestinal disease that can be fatal; in addition, body systems other than the gastrointestinal tract may be affected. The widespread use of antiretroviral therapy does appear to be having a beneficial effect on recovery from cryptosporidiosis and on the frequency of infection in human immunodeficiency virus-positive patients. Other diseases that are associated with increased risk of severe cryptosporidiosis, such as primary immunodeficiencies, most notably severe combined immunodeficiency syndrome, are also predominantly associated with T-cell defects. Of the remaining groups, children with acute leukemia seem to be most at risk from cryptosporidiosis. There is less evidence of severe complications in patients with other malignant diseases or in those receiving immunosuppressive chemotherapy.

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