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Biomedical subjects

Alan Rickinson

Publications and source records attributed to Alan Rickinson.

7 recordsLinked to original sources
PubMed2005

Cellular immunotherapy for viral infection after HSC transplantation.

Medical advances such as allogeneic transplantation can expose patients to periods of marked immunosuppression, during which viral infections are an important cause of morbidity and mortality. Control of infection will depend ultimately on the restoration of adequate antiviral immunity, and cellular immunotherapy is an attractive approach to improving immune protection. Developments in basic immunology have led to a greater understanding of the nature of protective immunity in immunocompetent donors, and this knowledge is now being used to direct immunotherapeutic protocols. Moreover, immunological techniques that have recently been developed as research tools, such as peptide-HLA tetramers and cytokine-secretion assays, have potential application for clinical use in this setting.

Antigens, Viral↗
PubMed2005

Epstein-Barr virus-induced B-cell transformation: quantitating events from virus binding to cell outgrowth.

Epstein-Barr virus (EBV) infection and growth activation of human B cells is central to virus biology and disease pathogenesis, but is poorly understood in quantitative terms. Here, using virus at defined m.o.i., the different stages of this process at the single-cell level are followed in vitro. Virus binding to the B-cell surface, assayed by quantitative PCR, is highly efficient, particularly at the low m.o.i. values that most likely reflect physiologic events in vivo. However, only 10-15 % of bound virus genomes reach the cell nucleus, as visualized by sensitive fluorescence in situ hybridization (FISH) assay; viral genomes acquired per cell nucleus range from 1 to >10, depending on the m.o.i. Thereafter, despite differences in initial genome load, almost all nuclear genome-positive cells then go on to express the virus-encoded nuclear antigen EBNA2, upregulate the cell activation antigen CD23 and transit the cell cycle. EBNA2-positive cells in the first cycle post-infection then grow out to lymphoblastoid cell lines (LCLs) just as efficiently as do cells limiting-diluted from already established LCLs. This study therefore identifies EBV genome delivery to the nucleus as a key rate-limiting step in B-cell transformation, and highlights the remarkable efficiency with which a single virus genome, having reached the nucleus, then drives the transformation programme.

B-Lymphocytes↗
PubMed2003

Reconstitution of the Epstein-Barr virus-specific cytotoxic T-lymphocyte response following T-cell-depleted myeloablative and nonmyeloablative allogeneic stem cell transplantation.

The recovery of circulating antigen-specific T-cell immunity to Epstein-Barr virus (EBV) was determined in ELIspot assays following allogeneic myeloablative or nonmyeloablative stem cell transplantation (MST/NST). In 8 of 12 MST patients receiving an alemtuzumab-treated graft, the frequency of the EBV-specific reactivities was similar to or greater than that seen in the healthy controls. A response was detectable in 3 of 6 and 6 of 9 patients by 3 and 6 months, respectively, and in all patients by one year following MST. In contrast, only 1 of 9 (95% confidence interval [CI], 0-2.8) patients made a detectable EBV-specific response by 6 months following NST conditioned with fludarabine, melphalan, and alemtuzumab. Responses were detected in 7 of 10 patients by 1 year after NST. Parallel surveillance demonstrated that other virus infections occurred more frequently and earlier after transplantation in NST patients. The use of alemtuzumab in vivo in the nonmyeloablative conditioning might have resulted in the delay in EBV-specific T-cell recovery and increased virus infections.

Alemtuzumab↗
PubMed2003

TAP-independent antigen presentation on MHC class I molecules: lessons from Epstein-Barr virus.

For recognition by CD8(+) lymphocytes, peptides derived from cytosolically processed antigen need to access MHC class I molecules en route to the target cell surface. This normally requires peptide transport into the endoplasmic reticulum via the transporter associated with antigen presentation (TAP) complex. However, as recent work with Epstein-Barr virus illustrates, TAP-independent presentation pathways also exist and are growing in number.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Identification of a TAP-independent, immunoproteasome-dependent CD8+ T-cell epitope in Epstein-Barr virus latent membrane protein 2.

We have identified an HLA-A2-restricted CD8(+) T-cell epitope, FLYALALLL, in the Epstein-Barr virus (EBV) latent membrane protein 2 (LMP2), an important target antigen in the context of EBV-associated malignancies. This epitope is TAP independent, like other hydrophobic LMP2-derived epitopes, but uniquely is dependent upon the immunoproteasome for its generation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Epstein-Barr virus-associated Burkitt lymphomagenesis selects for downregulation of the nuclear antigen EBNA2.

Epstein-Barr virus (EBV) is etiologically linked to endemic Burkitt lymphoma (BL), but its contribution to lymphomagenesis, versus that of the chromosomal translocation leading to c-myc gene deregulation, remains unclear. The virus's growth-transforming (Latency III) program of gene expression is extinguished in tumor cells, and only a single viral protein, the EBV nuclear antigen (EBNA)1, is expressed via the alternative Latency I program. It is not known if BL arises from a B-cell subset in which EBV naturally adopts a Latency I infection or if a clone with limited antigen expression has been selected from an EBV-transformed Latency III progenitor pool. Here we identify a subset of BL tumors in which the Latency III-associated EBNA promoter Wp is active and most EBNAs are expressed, but where a gene deletion has specifically abrogated the expression of EBNA2. This implies that BL can be selected from a Latency III progenitor and that the principal selection pressure is for downregulation of the c-Myc antagonist EBNA2.

B-Lymphocytes↗