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S R Riddell

Publications and source records attributed to S R Riddell.

65 records · Page 4Linked to original sources
PubMed1993

Herpes simplex virus infection of human fibroblasts and keratinocytes inhibits recognition by cloned CD8+ cytotoxic T lymphocytes.

CD8+ cytotoxic T lymphocytes (CTL) clones with specificity for herpes simplex virus (HSV) were derived from two donors with genital HSV-2 infection. These CTL clones specifically lysed HSV-infected autologous B lymphoblastoid cells, but not HSV-infected fibroblasts. Exogenous peptide loading sensitized both cell types to lysis by an HSV-specific CTL clone of known specificity. HSV infection rendered fibroblasts refractory to peptide sensitization. HSV infection also rendered fibroblasts and keratinocytes insensitive to lysis by allospecific CD8+ CTL clones. Lysis of B lymphoblastoid cells in this system was only slightly reduced by HSV infection. Reduction of fibroblast allospecific lysis was dose and time dependent and was blocked by acyclovir, indicating the involvement of a late HSV gene product. HSV caused a reduction of fibroblast cell surface HLA class I antigen, at least in part due to reduction of synthesis of heavy chain-beta 2 microglobulin heterodimers. These results suggest that HSV-induced blockade of antigen presentation by cutaneous cells to CD8+ CTL may be a mechanism by which HSV limits or evades the immune response of the host.

Animals↗
PubMed1992

Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones.

The adoptive transfer of antigen-specific T cells to establish immunity is an effective therapy for viral infections and tumors in animal models. The application of this approach to human disease would require the isolation and in vitro expansion of human antigen-specific T cells and evidence that such T cells persist and function in vivo after transfer. Cytomegalovirus-specific CD8+ cytotoxic T cell (CTL) clones could be isolated from bone marrow donors, propagated in vitro, and adoptively transferred to immunodeficient bone marrow transplant recipients. No toxicity developed and the clones provided persistent reconstitution of CD8+ cytomegalovirus-specific CTL responses.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1991

Development of a treatment regimen for human cytomegalovirus (CMV) infection in bone marrow transplantation recipients by adoptive transfer of donor-derived CMV-specific T cell clones expanded in vitro.

CMV infection represents a major cause of morbidity and mortality in immunosuppressed bone marrow transplant (BMT) recipients. Life-threatening CMV infection was found to occur only in patients who did not develop a CMV-specific CD8+ Tc response. Therefore, methods to clone and expand CMV-specific Tc were developed to facilitate analysis of the specificity of the CD8+ Tc response to CMV responsible for protective immunity in seropositive donors, and to permit adoptive transfer of in vitro expanded CMV-specific Tc derived from bone marrow donors into immunocompetent HLA-matched BMT recipients to augment resistance to CMV. The immunodominant class I-restricted Tc response present in healthy seropositive individuals was found to be specific for a conserved CMV antigen introduced into the cytoplasm and presented shortly following viral penetration and uncoating, and did not require endogenous viral gene expression and protein synthesis. Thus, the protective immune response to CMV mediates lysis of virally-infected cells prior to virion assembly. Processing of viral proteins and access to presentation in the context of class I MHC molecules immediately following infection of target cells was selective for internal virion proteins, such as the tegument protein pp65. By contrast, presentation by infected cells of GB, the major CMV envelope protein, or IE, the major regulatory protein, was delayed due to a requirement for endogenous synthesis in infected cells, and CD8+ Tc specific for these proteins were detected in low frequency as compared to the immundominant response.

Antigens, Viral↗
PubMed1991

Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease.

The high rate of severe cytomegalovirus (CMV) disease after bone marrow transplantation (BMT) is related to the profound immunodeficiency posttransplant. Because cytotoxic T lymphocytes (CTL) have been implicated in resistance to viral infections, we examined the restoration of the CMV-specific CTL response in 20 patients who received bone marrow from HLA-matched, CMV-seropositive donors. Blood specimens were obtained from patients at 1, 2, and 3 months after BMT and from the donors on a single occasion. Peripheral blood mononuclear cells were cocultured with CMV-infected donor-derived fibroblasts for 2 weeks and then tested for cytotoxicity against CMV-infected and uninfected autologous or HLA-mismatched fibroblasts. Cytolytic activity was detected in all 20 donors, with specificity for autologous CMV-infected targets demonstrable in 17 (median CMV-specific lysis at an effector:target ratio of 15:1 was 32%, range 18% to 83%). Specific lysis was mediated by CD8+, class I-restricted T cells, as shown by inhibition with anti-class I monoclonal antibody and by selective depletion of effector cells. By contrast, CMV-specific CTL were detected in only 10 of 20 patients after BMT (median lysis 29% at 3 months post-BMT). None of these 10 patients developed CMV pneumonia, whereas 6 of the 10 patients with an undetectable CMV-specific CTL response after BMT died with CMV pneumonia. These results demonstrate that restoration of CMV-specific CTL responses may require an extended time period after BMT in some patients, and that such patients are at increased risk of developing severe CMV disease. Approaches to reconstitute CMV immunity in BMT patients by adoptive transfer of CMV-specific CD8+ CTL clones derived from the bone marrow donor are now being pursued.

Adolescent↗
PubMed1991

T cells from tumor-immune mice nonspecifically expanded in vitro with anti-CD3 plus IL-2 retain specific function in vitro and can eradicate disseminated leukemia in vivo.

The therapeutic efficacy of adoptive immunotherapy of cancer has been shown to positively correlate with the dose of tumor-immune T cells transferred. Therefore, the success of this therapy is critically dependent on the ability to procure large numbers of functionally active T cells. Previous studies in animal models have shown that the limited therapeutic efficacy of a small number of immune T cells can be greatly enhanced by expansion of T cells in vitro to greater numbers before transfer in vivo. Optimal regimens for T cell expansion in vitro have generally employed the use of intermittent stimulation of the TCR with specific Ag followed by exogenous IL-2. The use of IL-2 alone does not provide for requisite episodic up-regulation of IL-2R. Stimulation of the invariant CD3 portion of the TCR/CD3 complex with antibody to CD3 (anti-CD3) represents an alternative method of up-regulating IL-2R and has been used to nonspecifically induce the growth of Ag-specific T cell lines and clones long-term in vitro with maintenance of function and specificity. The current study examined whether resting T cell populations containing small numbers of memory tumor-specific T cells could be rendered more effective in tumor therapy by nonspecific expansion in vitro with anti-CD3 plus IL-2. Spleens from C57BL/6 mice previously immunized to FBL-3, a syngeneic virus-induced leukemia, were nonspecifically stimulated with anti-CD3 plus IL-2. The resultant T cells were expanded in number, were nonlytic to FBL-3 but retained the ability to become lytic upon specific stimulation by FBL-3, and were effective in specific tumor therapy. The Ag-specific anti-tumor immune function declined on a per cell basis after each cycle of anti-CD3-induced T cell expansion. However, the approach resulted in a substantial increase in total T cell number and an overall net increase in the function of the effector T cell population. Thus, stimulation of tumor-immune T cell populations with anti-CD3 plus IL-2 represents a nonspecific method for expanding the number of specific effector T cells for cancer therapy.

Animals↗
PubMed1991

Class I MHC-restricted cytotoxic T lymphocyte recognition of cells infected with human cytomegalovirus does not require endogenous viral gene expression.

The human pathogen CMV, is a major cause of morbidity and mortality in immunocompromised hosts. The CD8+ class I-restricted CTL response to CMV assists in preventing progression of CMV infection to life-threatening disease; however, the viral Ag recognized by CD8+ CTL are not well characterized. In general, virus-specific CTL recognize endogenously synthesized viral proteins processed and presented associated with class I MHC molecules. Although proteins or inactivated virions have been experimentally delivered to the cytoplasm to result in class I MHC presentation, this mode of Ag delivery to the class I processing pathway after natural viral entry has not been documented in humans. Our data demonstrate that the CMV-specific class I-restricted CTL response in individuals latently infected with CMV is predominantly specific for selected structural virion proteins introduced into the cell after viral penetration and efficient recognition occurs in the absence of de novo viral gene expression. This CTL response may provide a biological advantage for limiting the spread of infection after CMV reactivation because infected cells are lysed before viral assembly.

Antigens, Viral↗
PubMed1990

The use of anti-CD3 and anti-CD28 monoclonal antibodies to clone and expand human antigen-specific T cells.

Antigen-specific T cell clones are useful reagents for studies of the fine specificity of antigen recognition and of potential therapeutic use in adoptive immunotherapy for human viral and malignant diseases. Culture methods which require antigen and APC for stimulation can be problematic for the generation and long-term growth of human virus and tumor-specific T cells. We have developed an alternative culture method using monoclonal antibodies to T cell activation molecules, CD3 and CD28, as stimulation to efficiently grow CD4+ and CD8+ antigen-specific T cells from single progenitors and expand T cell clones in long-term culture. This method alleviates the requirement for large amounts of viral or tumor antigens and MHC compatible APC to sustain the growth of virus and tumor-specific T cell clones, and, as demonstrated for CD8+ CMV-specific cytotoxic T cells, overcomes the difficulties cloning CD8+ T cells using virally infected cells as antigen-presenting cells. T cell clones generated and maintained with monoclonal antibody stimulation are rapidly expanded and retain antigen-specific responses after 3 months in culture, suggesting this approach may prove useful for growing large numbers of antigen-specific T cell clones for cellular immunotherapy.

Antibodies, Monoclonal↗
PubMed1986

Disseminated intravascular coagulation in lupus erythematosus responding to prednisone therapy.

A 48-year-old man with systemic lupus erythematosus (SLE) developed disseminated intravascular coagulation (DIC) with clinical bleeding. Since no other cause for DIC could be demonstrated, he was treated with prednisone, which rapidly corrected his DIC. This case demonstrates the need for a complete hematological investigation of patients with SLE who present with hemostatic abnormalities.

Disseminated Intravascular Coagulation↗
PubMedDate not supplied

Cytotoxic T cells specific for cytomegalovirus: a potential therapy for immunocompromised patients.

The occurrence of life-threatening infections, including cytomegalovirus (CMV) infection, in recipients of allogeneic bone marrow transplants is related to the severe and prolonged immunodeficiency that is present after transplantation. Studies performed in our laboratory of the recovery of CMV-specific T cell responses after bone marrow transplantation have demonstrated that CMV disease occurs exclusively in those patients with no reconstitution of CD8+ CMV-specific T cell responses. Methods of isolating class I major histocompatibility complex-restricted CD8+ CMV-specific T cell clones from healthy CMV-seropositive individuals with protective immunity have been developed. The majority of cytotoxic T cell clones isolated from several individuals recognize structural proteins of the virion that are presented by infected cells without requiring the expression of the viral gene. These results suggest this immunodominant response may be essential for maintaining the virus in a latent state in healthy CMV-seropositive individuals. Clinical trials have been initiated at our institution to investigate the potential for selective reconstitution of CMV-specific immunity in bone marrow transplant recipients by the adoptive transfer of CMV-specific T cell clones generated from the respective bone marrow donor.

Animals↗