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Robert Henderson

Publications and source records attributed to Robert Henderson.

16 recordsLinked to original sources
PubMed2006

Characterization of preexisting humoral immunity specific for two cancer-testis antigens overexpressed at the mRNA level in non-small cell lung cancer.

In order to establish a rationale for immunotherapy for lung cancer, we have investigated immunological characteristics of tumor-associated antigens (TAAs) discovered through molecular approaches. Preexisting Abs specific to these predicted TAAs were examined using specimens of lung pleural effusions (LPEs) and sera in non-small cell lung cancer (NSCLC) patients. The novel cancer-testis (CT) antigens L514S and L552S were highly expressed in approximately half of the NSCLC tissues and established cell lines examined. When lung cancer patients in the USA and Japan were screened, 13%, 17%, and 5% were found to have Abs specific to recombinant L514S, L552S, and NY-ESO-1 proteins, respectively, whereas 48 normal donors had no Abs to these three CT antigens. The Ab titers specific to recombinant L552S and L514S proteins were similar to, and slightly lower than, Abs specific to NY-ESO-1 in stage IV NSCLC patients. To further characterize the preexisting specific Abs, the epitopes were analyzed using 20-aa length peptides entirely covering both antigens. An epitope common to the patients' L514S-specific Abs was identified as aa 85-100 and multiple epitopes, including a major epitope (aa 141-160), were identified for L552S-specific Abs. The Ab epitopes thus identified are not found in human, animal, or bacterial proteins, other than L514S, L552S, or XAGE-1. These data clearly demonstrate that both molecularly defined CT antigens L514S and L552S are immunogenic, at least in terms of humoral responses, suggesting that both CT antigens are promising candidates for immunotherapy.

Amino Acid Sequence↗
PubMed2005

Case report: inspiratory muscle training in chronic critically ill patients--a report of two cases.

BACKGROUND AND PURPOSE: Inspiratory muscle weakness and fatigue has been documented following prolonged mechanical ventilation despite successful weaning from mechanical ventilation. This report describes the application of inspiratory muscle training in two patients following successful discharge from an intensive care unit (ICU) after prolonged mechanical ventilation. METHODS: Both patients undertook inspiratory muscle training in conjunction with standard physiotherapy rehabilitation. RESULTS: Improvements in inspiratory muscle strength and endurance, exercise tolerance and functional performance following twice-daily inspiratory muscle training were recorded. In both cases, an improvement in maximal inspiratory pressure (MIP) and maximal tolerated inspiratory load (MIP(load)) was found following training. CONCLUSION: These positive results indicate further research is needed to investigate the effect of inspiratory muscle training on respiratory function, exercise tolerance and functional performance, for the possible inclusion of inspiratory muscle training into the physiotherapy management of patients following prolonged mechanical ventilation.

Activities of Daily Living↗
PubMed2004

How T cells use LFA-1 to attach and migrate.

The T lymphocyte (or T cell) has classically been perceived to be a passive circular cell attaching to other cells or fibrils of the extracellular matrix when its integrins become activated. We now understand that the modus operandi of the T cell is migration. These cells are proving to be impressively fast migrators, clocking up basal speeds of approximately 10-15 microm/min which makes them amongst the fastest movers recorded to date. Therefore, migration is the business of the T cell and in this review we will discuss how its motility is regulated and what functions this activity makes possible.

Animals↗
PubMed2003

HSP110-HER2/neu chaperone complex vaccine induces protective immunity against spontaneous mammary tumors in HER-2/neu transgenic mice.

Heat shock proteins (HSPs) are shown to be strong immunoadjuvants, eliciting both innate and adaptive immune responses against cancers. HSP110 is related in sequence to HSP70 and is approximately 4-fold more efficient in binding to and stabilizing denatured protein substrates compared with HSP70. In the present study we evaluated the ability of a heat shock complex of HSP110 with the intracellular domain (ICD) of human HER-2/neu to elicit effective antitumor immune responses and to inhibit spontaneous mammary tumors in FVB-neu (FVBN202) transgenic mice. The HSP110-ICD complex was capable of breaking tolerance against the rat neu protein and inhibiting spontaneous mammary tumor development. This vaccine induced ICD-specific IFN-gamma and IL-4 production. Depletion studies revealed that CD8(+) T cells were involved in protection against challenge with mouse mammary tumors, whereas CD4(+) T cells revealed partial protection. Increased IgG2a Ab titer in the sera of tumor-free animals after vaccination and elevated CD4(+) CD25(+) regulatory T cells in the PBL of tumor-bearing animals suggested that IFN-gamma-producing Th1 cells may be responsible for partial protection of CD4(+) T cells against the mammary tumor challenge, whereas CD4(+)CD25(+) regulatory T cells (Th2 cells) may suppress the antitumor immune responses. Together, these results suggest that HSP110-ICD complex can elicit effective IFN-gamma-producing T cells against spontaneous mammary tumors and that up-regulation of CD4(+) CD25(+) regulatory T cells may prevent complete eradication of the tumor following immunotherapy.

Animals↗
PubMed2003

Targeted immunotherapy using reconstituted chaperone complexes of heat shock protein 110 and melanoma-associated antigen gp100.

This report defines a novel approach to heat shock protein vaccine formulation that takes advantage of the chaperoning property of heat shock protein hsp110 to efficiently bind a large protein substrate (specifically, human melanoma-associated antigen gp100) during heat shock. We demonstrate that hsp110 can form chaperone complexes with gp100 and prevent heat-induced aggregation of gp100. The resultant natural hsp110-gp100 complexes are strongly immunogenic as determined by their ability to elicit an antigen-specific IFN-gamma production and a cytotoxic T-cell response. Immunization with the hsp110-gp100 complex protected mice against subsequent challenge with human gp100-transduced B16 melanoma, which involves both CD4(+) and CD8(+) T-cell populations. Administration of the hsp110-gp100 vaccine also significantly suppressed the growth of established tumors in a therapeutic model. Furthermore, the hsp110-gp100 chaperone complex exhibited inhibitory effects on the progression of wild-type B16 tumor, suggesting that the induced immune response by human gp100 cross-reacts with mouse gp100. More importantly, the antitumor response obtained with the hsp110-gp100 complex is more potent than that obtained using Complete Freund's Adjuvant with gp100, whereas no response was observed against mouse hsp110 itself. Thus, the use of hsp110 to form natural chaperone complexes with tumor protein antigens such as gp100 represents a powerful approach to therapeutic vaccine formulation with significant potential for clinical application.

Animals↗
PubMed2003

Myeloid cell function in MRP-14 (S100A9) null mice.

Myeloid-related protein 14 (MRP-14) and its heterodimeric partner, MRP-8, are cytosolic calcium-binding proteins, highly expressed in neutrophils and monocytes. To understand the function of MRP-14, we performed targeted disruption of the MRP-14 gene in mice. MRP-14(-/-) mice showed no obvious phenotype and were fertile. MRP-8 mRNA but not protein is present in the myeloid cells of these mice, suggesting that the stability of MRP-8 protein is dependent on MRP-14 expression. A compensatory increase in other proteins was not detected in cells lacking MRP-8 and MRP-14. Although the morphology of MRP-14(-/-) myeloid cells was not altered, they were significantly less dense. When Ca(2+) responses were investigated, there was no change in the maximal response to the chemokine MIP-2. At lower concentrations, however, there was reduced responsiveness in MRP-14(-/-) compared with MRP-14(+/+) neutrophils. This alteration in the ability to flux Ca(2+) did not impair the ability of the MRP-14(-/-) neutrophils to respond chemotactically to MIP-2. In addition, the myeloid cell functions of phagocytosis, superoxide burst, and apoptosis were unaffected in MRP-14(-/-) cells. In an in vivo model of peritonitis, MRP-14(-/-) mice showed no difference from wild-type mice in induced inflammatory response. The data indicate that MRP-14 and MRP-8 are dispensable for many myeloid cell functions.

Animals↗
PubMed2002

Development of a recombinant HSP110-HER-2/neu vaccine using the chaperoning properties of HSP110.

Several studies have shown that when purified from a tumor, certain heat shock proteins (HSPs) can function as effective vaccines against the same tumor by virtue of their ability to bind tumor-specific peptides. However, only a small fraction of the associated peptides would be expected to be immunogenic, in addition to which, the clinical application of this vaccine requires the availability of a surgical specimen of sufficient quantity for purification of the HSP. The present study describes a new approach for the development of natural HSP vaccines that do not have these limitations. This approach uses a recombinant HSP that is noncovalently bound to a recombinant tumor protein antigen by heat shock. HSP110 has been selected for this purpose, because it has been shown to be a highly efficient molecular chaperone in binding to large protein substrates. We show that a "natural chaperone complex" between HSP110 and the intracellular domain (ICD) of human epidermal growth factor receptor 2 protein (HER-2)/neu is formed by heat shock. This HSP110-ICD vaccine elicited both CD8(+) and CD4(+) T-cell responses against ICD as determined by an antigen-specific IFN-gamma production in an enzyme-linked immunospot assay (ELISPOT). In vivo depletion studies revealed that the CD8(+) T-cell response was independent of CD4(+) T-cell help. The HSP110-ICD complex also significantly enhanced ICD-specific antibody responses relative to that seen with ICD alone. No CD8(+) T cell or antibody response was detected against HSP110. The use of recombinant HSP110 to form natural chaperone complexes with large protein antigens represents a new and powerful approach for the design of protein-targeted cancer vaccines.

Animals↗
PubMed2002

Mechanisms contributing to the activity of integrins on leukocytes.

Understanding how the integrins on leukocytes operate is important because these receptors control the activity of leukocytes in all phases of their lives. Thus integrins control leukocyte development and maturation in bone marrow, the circulation of naive cells in secondary lymphoid tissue, e.g. the lymph nodes, and leukocyte responses to inflammatory signals emanating from injured tissues. Using as an example LFA-1, which is expressed by all leukocytes, we outline how the activity of this integrin is modified to meet the challenges posed by these leukocyte activities. Briefly, we discuss three means by which LFA-1 is adapted to bind more efficiently to its chief ligand, ICAM-1. LFA-1 can undergo changes in conformation leading to increased affinity, can be clustered on the membrane and, finally, when activated can move into the lipid raft compartment of the membrane. The study of humans with the beta2 deficiency syndrome termed leukocyte adhesion deficiency (LAD)-1 and analysis of LFA-1 null mice has given further insight into integrin activation mechanisms and the in vivo roles of LFA-1 and other leukocyte integrins.

Animals↗