Three Cases of Lymphocytic Infiltration of the Eyelid

Lymphocytic infiltration of the skin (LIS), first reported by Jessner and Kanof in 1953, is a disease of unknown etiology characterized by erythematous papules and plaques on the head, neck, and upper back and histopathological findings of a normal epidermis with underlying lymphocytic infiltration of the reticular dermis without mucin deposition. A 69-year-old man and a 21-year-old woman presented with edematous indurative erythema of the left upper eyelid. Lymphocytic infiltration of the dermis with CD4+ T cell predominance was noted on biopsy. A 68-year-old man presented with a four-year history of recurrent edematous indurative erythema of the right upper eyelid that extended up to the right cheek. Predominantly dermal infiltration of CD8+ T lymphocytes was found on biopsy. We treated all three patients with 8–16 mg of methylprednisolone daily, and the erythema and induration improved. CD4+ T cells were predominant in the acute phase (patients 1 and 2), whereas CD8+ T cells were predominant in the chronic phase (patient 3). CD8+ T cells may be involved in LIS recurrence. Lymphocytic infiltration of the eyelid may be associated with isolated circumscribed, edematous, indurative, colorless lesions that are responsive to daily low-to-middle doses of oral methylprednisolone.

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Impaired IFN-γ Production by Viral Immunodominant Peptide-specific Tetramer+ CD8+ T Cells in HIV-1 Infected Patients is not Secondary to HAART

Clinical and Developmental Immunology ◽

10.1080/17402520400001611 ◽

2004 ◽

Vol 11 (3-4) ◽

pp. 287-298 ◽

Cited By ~ 4

Author(s):

Nattawat Onlamoon ◽

Kovit Pattanapanyasat ◽

Aftab A. Ansari

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Chronic Phase ◽

Prior History ◽

Specific Ctls ◽

Tnf Α ◽

History Of ◽

Ifn Γ ◽

Specific Peptide ◽

Hiv 1

Studies on PBMC samples from HIV-1 infected patients have shown that despite substantial number of HIV specific CTLs, these patients gradually progress to AIDS. The present study was conducted to determine whether this paradox was secondary to the influence of protease inhibitors being utilized by these patients. Thus, aliquots of PBMC samples from 10 HIV infected humans with no prior history of anti-retroviral drug therapy (ART) and 6 HIV-infected patients that had been on HAART for >1 year were analyzed for the frequency of HIV-1 Nef and Gag dominant peptide specific tetramer+ cells, respectively. The tetramer+ PBMCs were analyzed for their ability to synthesize specific peptide induced IFN-γ utilizing both the ELISPOT and the intracellular cytokine (ICC) assays. Results of the studies showed that there was an overall correlation between the frequency of Nef and Gag peptide tetramer+ cells and the frequency of IFN-γ synthesizing cells as assayed by either ICC or ELISPOT assay, markedly reduced values of IFN-γ synthesizing cells per unit tetramer+ cells were noted in both group of patients. These data suggest that the frequency of HIV-specific CD8+T cells is maintained during the chronic phase of infection, their ability to function is compromised and is not a reflection of ART. While the addition of IL-2, anti-CD40L and allogeneic cells led to partial increase in the ability of the tetramer+ cells to synthesize IFN-γ, the addition of IL-4, IL-12, anti-CD28 or a cocktail of anti-TGF-β, TNF-α and IL-10 failed to augment the IFN-γ response.

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Castleman's Disease: An Intrapulmonary Form with Intrafissural Development

The Scientific World JOURNAL ◽

10.1100/tsw.2009.110 ◽

2009 ◽

Vol 9 ◽

pp. 940-945 ◽

Cited By ~ 6

Author(s):

Hajer Racil ◽

Sana Cheikh Rouhou ◽

Olfa Ismail ◽

Saoussen Hantous-Zannad ◽

Nawel Chaouch ◽

...

Keyword(s):

Contrast Enhancement ◽

Castleman’S Disease ◽

Lower Lobe ◽

Unknown Etiology ◽

Castleman's Disease ◽

Curative Surgery ◽

Abnormal Shadow ◽

History Of ◽

Chest X Ray ◽

The Right

Castleman's disease (CD) is an uncommon, mainly benign, lymphoproliferative disorder of unknown etiology, mostly involving the mediastinum. Parenchymal lung involvement of the disease is exceedingly rare. We describe a case of CD in a 23-year-old woman with a 4-year history of recurring dyspnea and nonproductive cough, whose chest X-ray showed an abnormal shadow of the right hilum. Chest computed tomography confirmed the presence of a tissue-density mass of the right lower lobe, demonstrating poor contrast enhancement, associated with multiple laterotracheal and mediastinal lymphadenopathies. The patient underwent curative surgery, revealing a right hilar compressive mass, with an intrafissural development between the superior and middle lobes. Pneumonectomy was performed due to profuse bleeding. This case of CD is particular because of its unusual intrapulmonary location and its intrafissural development. Poor contrast enhancement is atypical in CD.

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Facial distortion due to chronic inflammation of unknown cause in a cat

Journal of Feline Medicine and Surgery Open Reports ◽

10.1177/2055116920957200 ◽

2020 ◽

Vol 6 (2) ◽

pp. 205511692095720

Author(s):

Lynelle R Johnson ◽

Sarah A Vidal ◽

Kelsey D Brust ◽

M Kevin Keel ◽

Michele A Steffey

Keyword(s):

Nasal Cavity ◽

Subcutaneous Tissue ◽

Mass Lesion ◽

Unknown Etiology ◽

Activity Levels ◽

Surgical Biopsy ◽

Nasal Bridge ◽

Upper Eyelid ◽

Frontal Sinuses ◽

The Right

Case summary An 8-year-old neutered male indoor cat was presented for evaluation of a year-long history of swelling over the bridge of the nose that extended from the subcutaneous tissue of the right upper eyelid to the dorsum of the skull. Intermittent regression of the mass lesion was reported with antibiotic or corticosteroid therapy; however, progressive swelling, malaise and hiding behavior persisted. CT revealed an aggressive osteolytic mass lesion in the right and left nasal cavities and extending into the frontal sinuses. Rhinoscopy using a 2.8 mm rigid telescope revealed somewhat normal-appearing turbinates rostrally and ventrally on the left side, with turbinate destruction on the right. After obtaining a biopsy from the right side of the nasal cavity, thick material filling the entire nasal cavity was visible caudally and was extracted endoscopically from a rostral approach. Surgical biopsy of the dorsal nasal bridge resulted in protrusion of inspissated material from the incision site. Rhinoscopic exploration revealed that the material extended into both frontal sinuses. Following extensive debridement and medical therapy, marked resolution of facial asymmetry was achieved. Relevance and novel information Facial distortion is often considered suggestive of a neoplastic process; however, it can also be seen with fungal and mycobacterial infections, and, in this case, an inflammatory condition of unknown etiology. In this cat, aggressive intervention and debridement of necrotic debris resulted in substantial bony remodeling of the skull and return to normal activity levels.

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CD45RC Expression of Circulating CD8+ T Cells Predicts Acute Allograft Rejection: A Cohort Study of 128 Kidney Transplant Patients

Journal of Clinical Medicine ◽

10.3390/jcm8081147 ◽

2019 ◽

Vol 8 (8) ◽

pp. 1147 ◽

Cited By ~ 3

Author(s):

Lemerle ◽

Garnier ◽

Planchais ◽

Brilland ◽

Subra ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Kidney Transplant ◽

Cd8 T Cells ◽

De Novo ◽

Predictive Biomarkers ◽

Transplant Patients ◽

History Of ◽

Kidney Transplant Patients ◽

A Prospective Study

Predictive biomarkers of acute rejection (AR) are lacking. Pre-transplant expression of CD45RC on blood CD8+ T cells has been shown to predict AR in kidney transplant (KT) patients. The objective of the present study was to study CD45RC expression in a large cohort of KT recipients exposed to modern immunosuppressive regimens. CD45RC expression on T cells was analyzed in 128 KT patients, where 31 patients developed AR, of which 24 were found to be T-cell mediated (TCMR). Pre-transplant CD4+ and CD8+ CR45RChigh T cell proportions were significantly higher in patients with AR. The frequency of CD45RChigh T cells was significantly associated with age at transplantation but was not significantly different according to gender, history of transplantation, pre-transplant immunization, and de novo donor specific anti-Human Leucocyte Antigen (HLA) antibody. Survival-free AR was significantly better in patients with CD8+ CD45RChigh T cells below 58.4% (p = 0.0005), but not different according to CD4+ T cells (p = 0.073). According to multivariate analysis, CD8+ CD45RChigh T cells above 58.4% increased the risk of AR 4-fold (HR 3.96, p = 0.003). Thus, pre-transplant CD45RC expression on CD8+ T cells predicted AR, mainly TCMR, in KT patients under modern immunosuppressive therapies. We suggest that CD45RC expression should be evaluated in a prospective study to validate its usefulness to quantify the pre-transplant risk of AR.

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Rituximab Administration before Allogeneic HSCT Is Associated with Accelerated T Cell Reconstitution after Transplantation: Kinetic Evidence for a Graft-Versus-Leukemia Effect

Blood ◽

10.1182/blood.v124.21.3905.3905 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3905-3905

Author(s):

Sakura Hosoba ◽

Christopher R. Flowers ◽

Catherine J Wu ◽

Jens R. Wrammert ◽

Edmund K. Waller

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cd8 T Cells ◽

Cell Subset ◽

Post Transplant ◽

T Cell Reconstitution ◽

Relative Value ◽

History Of

Abstract Introduction: Rituximab (R) administration results in depletion of blood B cells and suppression of B cell reconstitution for several months after, with suggestions that T cell reconstitution may also be impaired. We hypothesized that pre-transplant R would be associated with delayed B and T cell reconstitution after allo-HSCT compared with non-R-treated allo-HSCT recipients. Methods: We conducted a retrospective analysis of 360 patients who underwent allo-HSCT using BM or G-CSF mobilized PB. Recipients of cord blood, T cell depleted grafts and 2nd allo-HSCT were excluded. Analysis of lymphocyte subsets in at least one blood at 1, 3, 6, 12, and 24 months post-allo-HSCT was available for 255 eligible patients. Data on lymphocyte recovery was censored after DLI or post-transplant R therapy. Post-HSCT lymphocyte recovery in 217 patients who never received R (no-R) was compared to 38 patients who had received R before allo-HSCT (+R) including 12 CLL, 19 NHL, and 7 B-cell ALL patients. +R patients received a median of 9 doses of R with the last dose of R at a median of 45 days pre-transplant. Results: Mean lymphocyte numbers in the blood at 1, 3, 6, 12, and 24 months were B-cells: 55 ± 465/µL, 82 ± 159/µL, 150 ± 243/µL, 255 ± 345/µL, and 384 ± 369/µL (normal range 79-835); and T-cells: 65 ± 987/µL, 831 ± 667/µL, 1058 ± 788/µL, 1291 ± 985/µL, and 1477 ± 1222/µL (normal range 675-3085). Lymphocyte reconstitution kinetics did not vary significantly based upon the intensity of the conditioning regimen or related vs. unrelated donors allowing aggregation of patients in the +R and no-R groups (Figure). B cell reconstitution in the +R patients was higher at 1 month post-allo-HSCT (relative value of 143% p=0.008) and lower at 3 months post-transplant (19.2%, p=0.069) compared to no-R patients. Blood B cells in the +R group rebounded by the 6th month post-allo-HSCT and remained higher than the no-R group through the 24th month post-HSCT (197% at the 6th month, p=0.037). Higher levels of B-cells at 1 month in the +R group was due to higher blood B-cells at 1 month post-HSCT among 12 CLL patients compared with no-R patients (423%, p<0.001; Figure), while B-cell counts in the remaining +R patients (B-cell NHL and B-cell ALL) were lower than the no-R patients at both 1 and 3 months. Reconstitution of CD4+ and CD8+ T cells among +R patients were similar to no-R patients in the first month post-allo-HSCT and then rebounded to higher levels than the no-R group of patients (relative value 194%, p=0.077 at the 24th month for CD4+ T cell subset, and 224%, p=0.020 for CD8+ T cell subset; Figure). CLL patients had a striking increase in blood levels of donor-derived CD4+ and CD8+ T cells at 3 months post-transplant concomitant with the disappearance of blood B cells compared with no-R patients (relative value of 178% and 372%, p=0.018 and p=0.003, respectively; Figure). Long term T cell reconstitution remained higher for +R patients compared with no-R patients, even when CLL patients were excluded (relative value of 203%, p=0.005 at 24 months post-HSCT; Figure). Conclusions: We observed higher levels of blood B cells and T cells ³ 6 months post-allo-HSCT in +R patients compared with no-R patients. B cell recovery at 6 months post-transplant is consistent with clearance of residual plasma R given the 1-2 months half-life of R, and the median of 1.5 months between the last dose of R and allo-HSCT. The increased blood CD8+ T cells in the blood of CLL patients at 3 months post-allo-HSCT associated with clearance of the B-cells seen 1 month post-HSCT is consistent with a donor T cell-mediated GVL effect. Pre-transplant R therapy does not appear to have any long-term deleterious effect on immune reconstitution, indicating that post-allo-HSCT vaccination at ≥6 months may be efficacious. Figure: Kinetics of lymphocyte reconstitution after allo-HSCT varied by history of pre-transplant R administration and primary disease. Panels show mean counts of each lymphocyte subset at 1, 3, 6, 12 and 24 months post-allo-HSCT for: (1) B cell, (2) T cell, (3) CD4+ and (4) CD8+ T cells. Solid lines with triangle show no-R group; dashed lines with circles shows subgroups of CLL and NHL/ALL +R patients. Asterisks show p values from t-test of the comparison between CLL +R or the NHL/ALL +R patients with no-R patients. *p<0.05; ** p<0.01; *** p<0.001. Figure:. Kinetics of lymphocyte reconstitution after allo-HSCT varied by history of pre-transplant R administration and primary disease. Panels show mean counts of each lymphocyte subset at 1, 3, 6, 12 and 24 months post-allo-HSCT for: (1) B cell, (2) T cell, (3) CD4+ and (4) CD8+ T cells. Solid lines with triangle show no-R group; dashed lines with circles shows subgroups of CLL and NHL/ALL +R patients. Asterisks show p values from t-test of the comparison between CLL +R or the NHL/ALL +R patients with no-R patients. *p<0.05; ** p<0.01; *** p<0.001. Disclosures No relevant conflicts of interest to declare.

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Alterations in T-Cell Receptor Vβ Repertoire of CD4 and CD8 T Lymphocytes in Human Immunodeficiency Virus-Infected Children

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.10.1.53-58.2003 ◽

2003 ◽

Vol 10 (1) ◽

pp. 53-58 ◽

Cited By ~ 15

Author(s):

Monica Kharbanda ◽

Thomas W. McCloskey ◽

Rajendra Pahwa ◽

Mei Sun ◽

Savita Pahwa

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

T Cell ◽

T Lymphocytes ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Chronic Phase ◽

Cell Receptor ◽

Cd8 T Lymphocytes ◽

Immunodeficiency Virus

ABSTRACT Perturbations in the T-cell receptor (TCR) Vβ repertoire were assessed in the CD4 and CD8 T lymphocytes of human immunodeficiency virus (HIV)-infected children who were receiving therapy during the chronic phase of infection by flow cytometry (FC) and PCR analysis. By FC, representation of 21 TCR Vβ subfamilies was assessed for an increased or decreased percentage in CD4 and CD8 T cells, and by PCR, 22 TCR Vβ subfamilies of CD4 and CD8 T cells were analyzed by CDR3 spectratyping for perturbations and reduction in the number of peaks, loss of Gaussian distribution, or clonal dominance. The majority of the TCR Vβ subfamilies were examined by both methods and assessed for deviation from the norm by comparison with cord blood samples. The CD8-T-lymphocyte population exhibited more perturbations than the CD4 subset, and clonal dominance was present exclusively in CD8 T cells. Of the 55 total CD8-TCR Vβ families classified with clonal dominance by CDR3 spectratyping, only 18 of these exhibited increased expression by FC. Patients with high numbers of CD8-TCR Vβ families with decreased percentages had reduced percentages of total CD4 T cells. Increases in the number of CD4-TCR Vβ families with increased percentages showed a positive correlation with skewing. Overall, changes from normal were often discordant between the two methods. This study suggests that the assessment of HIV-induced alterations in TCR Vβ families at cellular and molecular levels yields different information and that our understanding of the immune response to HIV is still evolving.

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Early Mycosis Fungoides Lesions with Increased CD3-CD4+ Histiocytes Are Associated with Dyslipidemia and Use of Statins

Blood ◽

10.1182/blood.v126.23.4609.4609 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4609-4609

Author(s):

Chee Won Oh ◽

Carlos Torres-Cabala ◽

Mikyoung Chang ◽

Madeleine Duvic

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Cd8 T Cells ◽

Research Funding ◽

Skin Lesions ◽

Medication History ◽

Advisory Committees ◽

History Of ◽

Skin Biopsies

Abstract Background The term "histiocyte" includes cells of the monocyte/macrophage series as antigen processing cells and the Langerhans cell/DC series as antigen-presenting cells. At least three DC subsets exist in skin: two expressing either CD1a or CD14 are dermal and Langerhans cells expressing CD1a are epidermal. Since the phenotype of histiocytic cells is typically CD3-CD4+, an estimation of the CD4+ histiocytic population can be made by comparing the numbers of CD3+ T cells with CD4+ cells. Programmed Cell Death 1 (PD-1) is an inhibitory receptor expressed on T cells, B cells, and some myeloid cells. During chronic antigen exposure, expression of PD-1 is sustained. Statins, inhibitors of cholesterol biosynthesis, are immunomodulatory agents acting on T cells and DCs, but their effects on skin immunology are unknown. Objectives To investigate whether infiltrates of CD3-CD4+histiocytes in early mycosis fungoides (MF) lesional skin biopsies are associated with any other factors, including history of medication and to reveal their histopathological pattern. Methods From Jan to Dec 2014, we identified cases of early MF from the clinic in which CD4+ cells exceeded CD3+ cells with biopsies to identify increased histiocytic population. Exclusion criteria included Sézary syndrome, granulomatous MF, T cell receptor beta monoclonality, abnormal T cell populations by flow cytometry, retinoid treatment, and progression of disease after treatment (n=12). Clinical and laboratory findings were retrospectively reviewed. Skin biopsies stained for H&E, CD3, CD4, CD7, and CD8 were reviewed. In 3 cases with paraffin blocks available, immunohistochemical stains for CD68, CD1a, CD163, PD-1, and PD-1 ligand PD-L1 were done. Results Clinical manifestations of early MF were pink scaly patches (9/12), capillaritis (2/12), and annular erythema - like patches (1/12). Eleven also had an increased monocytes in peripheral blood. All cases had a medication history of taking statins (atorvastatin 5/12; simvastatin 2/12; rosuvastatin 1/12) for dyslipidemia (hypercholesterolemia 7/12; both hypercholesterolemia and hypertriglyceridemia 3/12). In 9/12, symptoms persisted after MF treatment. A lichenoid or superficial perivascular lymphohistiocytic infiltration was observed in skin lesions. Focal basal vacuolization was found in all 12 patients. Upper dermal perivascular extravasation of RBCs suggesting vasculopathy was also found in 12/12 cases. All twelve cases showed predominant CD4+ T cells compared to CD8+ T cells in dermis and the CD4+ T cells were more prominent in dermis rather than in epidermis. CD7+ T cells were preserved (3/12) or partially lost (9/12). In all 3 cases, macrophage markers CD68 and CD163 were positive in dermal infiltrates. CD1a+ DCs were increased in both epidermis and dermis in all 3/3. Only one case of three showed PD1/PD-L1+ T cells in dermis. Discussion and Conclusion All our cases had a medication history of statins for dyslipidemia. Of interest, skin biopsies showed a vasculopathy previously reported during high-dose atorvastatin treatment (Tehrani et al, 2013) and infiltration of CD4/CD8+ T cells, CD1a+DCs and CD163/CD68+ macrophages. We hypothesize that statins or dyslipidemia in early MF were associated with cutaneous T cell immune reaction. In support of our hypothesis that dyslipidemia is associated with histiocytosis, we found a report of nine cases of granulomatous pigmented purpuric dermatosis with concurrent hyperlipidemia (Battle et al, 2015). Cholesterol induces monocytosis and M1 macrophages in mice. One study showed that predominant migration of mature CD1a+ DC is associated with release of IL-12p70 and efficient expansion of Th 1 cells and functional CD8+ T cells. On the contrary, IL-10 up-regulates migration of immature CD14+ DC, expression of the M2 macrophage marker CD163, poor expansion of CD4+ and CD8+ T cells, and skewing of Th responses conducive to expression of PD-L1. We cannot know whether skin lesions are secondary to hyperlipidemia or to treatment with statins. Although M1 and M2 macrophages can be distinguished by diverse markers, none of these antigens are suitable for single-marker identification by immunohistochemistry in paraffin embedded tissue blocks. Further study of the cutaneous effect and immunologic mechanisms leading to increased expression of DCs and T cell dysfunction after statin medication is necessary. Disclosures Duvic: Oncoceutics: Research Funding; Therakos: Research Funding, Speakers Bureau; Huya Bioscience Int'l: Consultancy; Tetralogics SHAPE: Research Funding; Innate Pharma: Research Funding; Cell Medica Ltd: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; MiRagen Therapeutics: Consultancy; Soligenics: Research Funding; Allos (spectrum): Research Funding; Array Biopharma: Consultancy; Spatz Foundation: Research Funding; Rhizen Pharma: Research Funding; Eisai: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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NK cells negatively regulate CD8 T cells to promote immune exhaustion and chronic Toxoplasma gondii infection

10.1101/864272 ◽

2019 ◽

Author(s):

Daria L. Ivanova ◽

Ryan Krempels ◽

Stephen L. Denton ◽

Kevin D. Fettel ◽

Giandor M. Saltz ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Toxoplasma Gondii ◽

Nk Cells ◽

Cell Population ◽

Cd8 T Cells ◽

Nk Cell ◽

Chronic Phase ◽

Cd8 T Cell ◽

Cell Compartment

AbstractNK cells regulate CD4+ and CD8+ T cells in acute viral infection, vaccination and the tumor microenvironment. NK cells also become exhausted in chronic activation settings. The mechanisms causing these ILC responses and their impact on adaptive immunity are unclear. CD8+ T cell exhaustion develops during chronic Toxoplasma gondii (T. gondii) infection resulting in parasite reactivation and death. How chronic T. gondii infection impacts the NK cell compartment is not known. We demonstrate that NK cells do not exhibit hallmarks of exhaustion. Their numbers are stable and they do not express high PD1 or LAG3. NK cell depletion with anti-NK1.1 is therapeutic and rescues chronic T. gondii infected mice from CD8+ T cell exhaustion dependent death, increases survival after lethal secondary challenge and reduces parasite reactivation. Anti-NK1.1 treatment increased polyfunctional CD8+ T cell responses in spleen and brain and reduced CD8+ T cell apoptosis. Chronic T. gondii infection promotes the development of a modified NK cell compartment, which does not exhibit normal NK cell behavior. This splenic CD49a-CD49b+NKp46+ NK cell population develops during the early chronic phase of infection and increases through the late chronic phase of infection. They are Ly49 and TRAIL negative and are enriched for expression of CD94/NKG2A and KLRG1. They do not produce IFNγ, are IL-10 negative, do not increase PDL1 expression, but do increase CD107a on their surface. They are also absent from brain. Based on the NK cell receptor phenotype we observed NKp46 and CD94-NKG2A cognate ligands were measured. Activating NKp46 (NCR1-ligand) ligand increased and NKG2A ligand Qa-1b expression was reduced. Blockade of NKp46 also rescued the chronically infected mice from death. Immunization with a single dose non-persistent 100% protective T. gondii vaccination did not induce this cell population in the spleen, suggesting persistent infection is essential for their development. We hypothesize chronic T. gondii infection induces an NKp46 dependent modified NK cell population that reduces functional CD8+ T cells to promote persistent parasite infection in the brain. NK cell targeted therapies could enhance immunity in people with chronic infections, chronic inflammation and cancer.

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Low Risk of Infectious Events in Patients (Pts) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Treated with Dasatinib.

Blood ◽

10.1182/blood.v114.22.3291.3291 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3291-3291

Author(s):

Ali M Al -Ameri ◽

Hagop Kantarjian ◽

Elizabeth Burton ◽

Susan O'Brien ◽

Farhad Ravandi ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Research Funding ◽

Opportunistic Infections ◽

Antiviral Treatment ◽

Significant Risk ◽

Chronic Phase ◽

Total Daily Dose ◽

Coagulase Negative Staphylococcus ◽

Dependent Manner

Abstract Abstract 3291 Poster Board III-1 Background: In vitro, dasatinib inhibits proliferation of CD8+ T cells in a dose-dependent manner, associated with decreased secretion of interferon-gamma and granzyme B, as well as arrest of CD8+ T cells in the G0/G1 phase of cell cycle (Blake SJ Blood 2008 Feb.1;111(3):1366-77)). Inhibition of CD8+ T cells has also been shown in blood samples from patients receiving dasatinib compared with their T cell status prior to dasatinib (Cara K.Fraser, Ex.Hema.2009; 37:256-265). These immunosuppressive properties have raised concerns about potential high risk for opportunistic and other infections among patients treated with dasatinib. Aim: Investigate the frequency and characteristics of infectious events in pts with CML in CP treated with dasatinib. Methods: Records from 55 consecutive patients with CML CP treated with dasatinib after imatinib failure were analyzed. Median time from diagnosis to the start of dasatinib therapy was 66 months. The characteristics and management of infectious complications were analyzed for each pt. Results: After a median follow-up of 6 months from the start of therapy, 31 (56%) pts had 53 episodes of infections (Table 1). These included 20 of 34 (58.8%) pts treated with a total daily dose of 140 mg/day, 6 of 8 (75%) treated with 100 mg/day, 2 of 3 (66.7%) treated with 70 mg/day. The one pt treated with 180 mg/day and both patients treated with a dose of 30 mg/day or less (in phase I study) had infections. Most of the infections were localized and not considered related to dasatinib therapy. Blood cultures were done for 5 of the infections (9.4%): 3 were negative and 2 positive (one for coagulase negative staphylococcus and one for streptococcus). Wound cultures were done in 3 pts: one with positive staphylococcus of the foot, one with staphylococcus positive bursitis of the elbow, and one cellulitis with a positive result for MRSA. Other positive cultures included one with a sputum culture positive for MRSA and one with E .coli in a urine culture. 29 (54.7%) of the infectious events required antibiotic therapy; 3 required IV antibiotics, (one with cellulitis, one with an ear infection and one with pneumonia) and one pt needed antiviral treatment for H. zoster. Four patients needed hospital admission; 2 pts had pneumonia, one had cellulitis and positive blood culture, and one had fever and plural effusion. Infections resolved in all 31 pts without complications. ANC at the time of infection was <1 ×109/L in 3 patients (5.5%). Conclusions: This analysis shows that although many patients may develop infections during the course of therapy with dasatinib, these are overwhelmingly common infections, minor, and not related to dasatinib therapy. Opportunistic infections were rare. There is no evidence that dasatinib induces a significant risk of infections in patients with CML in CP. Disclosures: Kantarjian: BMS: Research Funding. Rios:BMS: Honoraria. Cortes:BMS: Research Funding.

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Macaques vaccinated with live-attenuated SIV control replication of heterologous virus

Journal of Experimental Medicine ◽

10.1084/jem.20081524 ◽

2008 ◽

Vol 205 (11) ◽

pp. 2537-2550 ◽

Cited By ~ 115

Author(s):

Matthew R. Reynolds ◽

Andrea M. Weiler ◽

Kim L. Weisgrau ◽

Shari M. Piaskowski ◽

Jessica R. Furlott ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Chronic Phase ◽

Viral Control ◽

Mhc I ◽

Challenge Virus ◽

Recombinant Viruses ◽

Aids Vaccine ◽

Aids Epidemic ◽

Heterologous Challenge

An effective AIDS vaccine will need to protect against globally diverse isolates of HIV. To address this issue in macaques, we administered a live-attenuated simian immunodeficiency virus (SIV) vaccine and challenged with a highly pathogenic heterologous isolate. Vaccinees reduced viral replication by ∼2 logs between weeks 2–32 (P ≤ 0.049) postchallenge. Remarkably, vaccinees expressing MHC-I (MHC class I) alleles previously associated with viral control completely suppressed acute phase replication of the challenge virus, implicating CD8+ T cells in this control. Furthermore, transient depletion of peripheral CD8+ lymphocytes in four vaccinees during the chronic phase resulted in an increase in virus replication. In two of these animals, the recrudescent virus population contained only the vaccine strain and not the challenge virus. Alarmingly, however, we found evidence of recombinant viruses emerging in some of the vaccinated animals. This finding argues strongly against an attenuated virus vaccine as a solution to the AIDS epidemic. On a more positive note, our results suggest that MHC-I–restricted CD8+ T cells contribute to the protection induced by the live-attenuated SIV vaccine and demonstrate that vaccine-induced CD8+ T cell responses can control replication of heterologous challenge viruses.

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