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1.  Febrile reactions occurring with second cycle of high-dose melphalan and SCT in patients with AL amyloidosis: a ‘melphalan recall’ reaction 
Bone marrow transplantation  2009;45(1):21-24.
Aggressive treatment with high-dose i.v. melphalan followed by auto-SCT (HDM/SCT) is effective in inducing hematological and clinical remissions, and in extending survival in AL amyloidosis. Tandem cycles of HDM/SCT have been shown to increase hematologic complete response rates in patients with AL amyloidosis. Between April 1994 and July 2008, 57 patients with AL amyloidosis at the Boston University Medical Center were treated with a second cycle of HDM/SCT after failing to achieve a complete response after a first transplantation. A total of 11 of 57 patients (19%) treated with tandem transplantation developed high fever 12–24 h after melphalan administration. The average peak temperature was 39.1 °C. Other clinical features include hypotension, acute renal failure and skin rash. No infectious etiology was identified. One of the patients had serum available for measurement of cytokines before, during and after the febrile reaction. The concentration of several pro-inflammatory cytokines, including IL-6 and TNFα, increased significantly, showing a clear physiological response correlating with the clinical findings. We conclude that an unusual cytokine-mediated febrile reaction can occur in patients with AL amyloidosis exposed to a second cycle of high-dose melphalan, which we have termed a ‘melphalan recall’ reaction.
doi:10.1038/bmt.2009.94
PMCID: PMC3672063  PMID: 19421171
AL amyloidosis; stem cell transplantation; melphalan recall
2.  Cancer-testis antigen expression and immunogenicity in AL amyloidosis 
Blood Cancer Journal  2012;2(9):e90-.
Light-chain amyloidosis (AL) is a plasma cell dyscrasia closely related to multiple myeloma. In multiple myeloma, the cancer-testis antigens (CTAs) CT7 (MAGE-C1), CT10 (MAGE-C2) and MAGE-A CTAs are expressed in up to 80% of cases. In this study, we investigated the expression and immunogenicity of several CTAs in patients with AL amyloidosis in a total of 38 bone marrow specimens by employing standard immunohistochemistry techniques on paraffin-embedded archival tissues. Plasma samples from 35 patients (27 with matched bone marrow samples) were also analyzed by ELISA for sero reactivity to a group of full-length CTA proteins. CT7 was present in 25/38 (66%) while CT10 was demonstrated in 3/38 and GAGE in 1/38 AL amyloid cases. The expression pattern was mostly focal. There were no significant differences with regard to organ involvement, response to treatment, or prognosis in CTA positive compared to negative cases. None of the specimens showed spontaneous humoral immunity to CT7, but sero reactivity was observed in individual patients to other CTAs. This study identifies CT7 as the prevalent CTA in plasma cells of patients with AL amyloidosis. Further analyses determining the biology of CTAs in AL amyloidosis and their value as potential targets for immunotherapy are warranted.
doi:10.1038/bcj.2012.32
PMCID: PMC3461704  PMID: 22983433
AL amyloidosis; cancer-testis antigens; stem cell transplantation
3.  Immunological memory and acquired immunodeficiency syndrome pathogenesis. 
Infection with the human immunodeficiency virus results in profound perturbations in immunological memory, ultimately resulting in increased susceptibility to opportunistic infections and acquired immunodeficiency syndrome (AIDS). We have used rhesus macaques infected with the simian immunodeficiency virus (SIV) as a model to understand better the effects of AIDS virus infection on immunological memory. Acute infection with SIV resulted in significant deficits in CD4+ helper responses to cytomegalovirus (CMV) as well as CMV-specific cytotoxic T-lymphocyte and neutralizing antibody responses. Reactivation of CMV was associated with high levels of SIV replication and suppression of both T-helper and cytotoxic responses to CMV. We have also studied the effects of SIV infection on T-cell turnover in non-human primates. T-cell turnover was evaluated using the nucleoside analogue bromodeoxyuridine (BrdU) in combination with five-colour flow cytometric analysis. T cells in normal animals turned over at relatively rapid rates, with memory cells turning over more quickly than naive cells. In SIV-infected animals, the labelling and elimination rates of both CD4+ and CD8+ BrdU-labelled cells were increased by two- to threefold compared with normal controls. Further analysis of immunological memory in non-human primates should offer the opportunity to extend immunological insights from murine models to the pathogenesis and prevention of AIDS.
PMCID: PMC1692746  PMID: 10794059
4.  Enhanced downregulation of Lck-mediated signal transduction by a Y114 mutation of herpesvirus Saimiri tip. 
Journal of Virology  1997;71(9):7092-7096.
Tip of herpesvirus saimiri associates with Lck and downregulates Lck function in cellular signal transduction. In this report, we demonstrate that mutation of tyrosine 114 of Tip significantly increases Lck-binding activity. This mutant exhibits a dramatic increase in the suppression of cellular tyrosine phosphorylation and surface expression of lymphocyte antigens in comparison with wild-type Tip. In addition, the expression of TipY114 converted the transforming morphology of fibroblasts induced by oncogenic F505 Lck to a normal cellular morphology. These results further support a mechanism by which the association of Tip with Lck negatively regulates Lck-mediated signal transduction.
PMCID: PMC192003  PMID: 9261442
5.  A role for natural simian immunodeficiency virus and human immunodeficiency virus type 1 nef alleles in lymphocyte activation. 
Journal of Virology  1997;71(8):6094-6099.
A T-lymphoid cell line termed 221 was derived from a rhesus monkey infected with herpesvirus saimiri. Growth of 221 cells was dependent on the addition of interleukin-2 (IL-2) to the culture medium. In the absence of IL-2, 221 cells arrested in G0-G1 but did not die. Simian immunodeficiency virus (SIV) replicated efficiently in IL-2-stimulated 221 cells whether or not the nef gene was present. In the absence of IL-2, nef-containing SIV replicated 8 to 100 times more efficiently in 221 cells than did the same virus lacking nef. nef-containing virus preferentially stimulated the production of IL-2 from 221 cells. HIV-1 nef and v-ras genes, but not the c-ras gene, were shown to substitute functionally for SIV nef when tested as recombinant viruses in this assay system. These results demonstrate a role for natural nef in causing lymphoid cell activation, and they provide a system for delineating the biochemical mechanisms responsible for this activation.
PMCID: PMC191869  PMID: 9223503
6.  Transduction of CD34+ hematopoietic progenitor cells with an antitat gene protects T-cell and macrophage progeny from AIDS virus infection. 
Journal of Virology  1997;71(4):2740-2746.
Transduction of hematopoietic stem cells with genes that inhibit human immunodeficiency virus (HIV) replication has the potential to reconstitute immune function in individuals with AIDS. We evaluated the ability of an autoregulated gene, antitat, to inhibit replication of simian immunodeficiency virus (SIV) and HIV type 1 (HIV-1) in hematopoietic cells derived from transduced progenitor cells. The antitat gene expresses an antiviral RNA encoding polymeric Tat activation response elements in combination with an antisense tat moiety under the control of the HIV-1 long terminal repeat. CD34+ hematopoietic progenitor cells were transduced with a retroviral vector containing the antitat gene and then cultured under conditions that support in vitro differentiation of T cells or macrophage-like cells. Rhesus macaque CD4+ T cells and macrophage-like cells derived from CD34+ bone marrow cells transduced with the antitat gene were highly resistant to challenge with SIV, reflecting a 2- to 3-log reduction in peak SIV replication compared with controls. Similarly, human CD4+ T cells derived from CD34+ cord blood cells transduced with antitat were also resistant to infection with HIV-1. No evidence for toxicity of the antitat gene was observed in any of five different lineages derived from transduced hematopoietic cells. These results demonstrate that a candidate therapeutic gene introduced into hematopoietic progenitor cells can retain the ability to inhibit AIDS virus replication following T-cell differentiation and support the potential use of the antitat gene for stem cell gene therapy.
PMCID: PMC191396  PMID: 9060627
7.  Comparative analysis identifies conserved tumor necrosis factor receptor-associated factor 3 binding sites in the human and simian Epstein-Barr virus oncogene LMP1. 
Journal of Virology  1996;70(11):7819-7826.
Nonhuman primates are naturally infected with a B-lymphotropic herpesvirus closely related to Epstein-Barr virus (EBV). These simian EBV share considerable genetic, biologic, and epidemiologic features with human EBV, including virus-induced tumorigenesis. However, latent, transformation-associated viral genes demonstrate marked sequence divergence among species despite the conserved functions. We have cloned the latent membrane protein 1 (LMP1) homologs from the simian EBV naturally infecting baboons (cercopithicine herpesvirus 12, herpesvirus papio) and rhesus monkeys (cercopithicine herpesvirus 15) for a comparative study with the human EBV oncogene. The transmembrane domains are well conserved, but there is striking sequence divergence of the carboxy-terminal cytoplasmic domain essential for B-cell immortalization and interaction with the tumor necrosis factor receptor signaling pathway. Nevertheless, the simian EBV LMP1s retain most functions in common with EBV LMP1, including the ability to induce NF-(kappa)B activity in human cells, to bind the tumor necrosis factor-associated factor 3 (TRAF3) in vitro, and to induce expression of tumor necrosis factor-responsive genes, such as ICAM1, in human B lymphocytes. Multiple TRAF3 binding sites containing a PXQXT/S core sequence can be identified in the simian EBV LMP1s by an in vitro binding assay. A PXQXT/S-containing sequence is also present in the cytoplasmic domain of the Hodgkin's disease marker, CD30, and binds TRAF3 in vitro. The last 13 amino acids containing a PXQXT/S sequence are highly conserved in human and simian EBV LMP1 but do not bind TRAF3, suggesting a distinct role for this conserved region of LMP1. The conserved TRAF3 binding sites in LMP1 and the CD30 Hodgkin's disease marker provides further evidence that a TRAF3-mediated signal transduction pathway may be important in malignant transformation.
PMCID: PMC190852  PMID: 8892903
8.  Efficient lysis of human immunodeficiency virus type 1-infected cells by cytotoxic T lymphocytes. 
Journal of Virology  1996;70(9):5799-5806.
Numerous studies of human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocytes (CTL) have examined their ability to recognize B-cell lines expressing recombinant HIV-1 proteins, but relatively few data regarding the lysis of HIV-1-infected cells by CTL are available. We studied the ability of HIV-1-specific CTL clones of defined epitope specificity and HLA restriction to lyse infected CD4+ cells at serial time points following infection. CD4+ cell lines were acutely infected with HIV-1 IIIB at a high multiplicity of infection, and the kinetics of cell lysis were examined and compared with the kinetics of viral replication. Intracellular HIV-1 p24 expression was detected by 1 to 2 days after infection, reaching over 98% positive cells by day 4. Recognition of the infected cells by HLA A2- and B14-restricted CTL clones closely paralleled intracellular p24 expression and preceded peak virion production. The maximal levels of lysis with Gag-, reverse transcriptase-, and envelope-specific clones were different, however. The Gag- and envelope-specific clones lysed infected cells at levels equivalent to peptide-sensitized controls, whereas lysis by the reverse transcriptase-specific clones plateaued at a lower level. Peptide titration curves indicated that this effect was not due to differences in sensitivity to the cognate epitopes for the different clones. Although HIV-1 infection induced an approximately 50% decrease in class I HLA expression on the surface of infected cells, lysis by CTL clones was unaffected. These studies indicate that HIV-1-specific CTL can efficiently lyse HIV-1-infected CD4+ cells and suggest that the partial downregulation of class I molecules in infected cells does not significantly affect recognition by CTL.
PMCID: PMC190594  PMID: 8709196

Results 1-8 (8)