Biomedical subjects
Publications and source records attributed to Phillip Wong.
Intravascular lymphomatosis (IVL) is a rare, yet important, cause of a variety of unexplained neurological syndromes. In this clinical context, the only clue to the diagnosis may be a significantly raised plasma lactate dehydrogenase (LDH) on a background of clinical features of a systemic illness.
CASE STUDY: A caucasian woman aged 79 years, with a history of hypertension, hyperlipidaemia, and osteoarthritis, was referred for assessment of osteoporosis and generalised musculoskeletal pain after surgery for a right midshaft femoral fracture. Further history revealed she had suffered nonspecific musculoskeletal pain, particularly of the pelvic girdle, and unsteady gait for many weeks, but denied suffering any falls. She had limited mobility due to osteoarthritis of both knees. She had been mostly housebound and was on an animal product restricted diet in view of her history of hypercholesterolaemia. Initial X-rays confirmed an incomplete fracture of the midshaft of the right femur. She had an orthopaedic review, and subsequent bone scan and X-rays (Figure 1) revealed incomplete fractures of the midshaft of both femurs and the seventh rib. She was managed conservatively (alendronate 70 mg per week) and progress was closely monitored. Three weeks later, she presented to the emergency department with worsening right thigh pain and difficulty in weightbearing. X-rays revealed an extension of the right femoral fracture traversing the entire cortex that required surgery. Physical examination revealed a mild thoracic kyphosis. There was no muscle or bone tenderness, proximal muscle weakness, or other significant abnormality. The plasma biochemistry revealed: mild hypocalcaemia (1.98 mmol/L), hypophoshataemia (0.7 mmol/L), raised alkaline phosphatase (ALP) (216 iu/L), low 25-hydroxyvitamin D (250HD) (22 nmol/L), and a mildly raised parathyroid hormone (PTH) level (8 pmol/L). Thyroid, renal, and liver functions were normal. The patient was treated with nine capsules of Ostelin 1000 per day, which was tapered over 8 weeks to one capsule. The repeat plasma 25OHD after 6 weeks was 56 nmol/L, and her musculoskeletal symptoms were completely resolved. There was normalisation of biochemical abnormalities and X-rays demonstrated healing of both femoral fractures. A bone biopsy taken at the time of surgery revealed an increased amount of osteoid. However, undecalcified bone sections were not examined, nor was quantitative histomorphometry performed. Dual energy X-ray absortiometry (DEXA) scan revealed a T-score of -3.32 at the hip and -1.38 at the lumbar spine. Corresponding Z-scores were -1.05 and -0.7.
Epithelial cells at environmental interfaces provide protection from potentially harmful agents, including pathogens. In addition to serving as a physical barrier and producing soluble mediators of immunity, such as cytokines or antimicrobial peptides, these cells are thought to function as nonprofessional APCs. In this regard, intestinal epithelial cells are particularly prominent because they express MHC class II molecules at the site of massive antigenic exposure. However, unlike bone marrow-derived professional APC, such as dendritic cells or B cells, little is known about the mechanisms of MHC class II presentation by the nonprofessional APC in vivo. The former use the lysosomal cysteine protease cathepsin S (Cat S), whereas thymic cortical epithelial cells use cathepsin L (Cat L) for invariant chain degradation and MHC class II maturation. Unexpectedly, we found that murine Cat S plays a critical role in invariant chain degradation in intestinal epithelial cells. Furthermore, we report that nonprofessional APC present a class II-bound endogenous peptide to naive CD4 T cells in vivo in a Cat S-dependent fashion. These results suggest that in vivo, both professional and nonprofessional MHC class II-expressing APC use Cat S, but not Cat L, for MHC class II-mediated Ag presentation.
Immunosuppressive agents in current use are nonspecific. The capacity to delete specific CD8 T-cell clones of unique specificity could prove to be a powerful tool for dissecting the precise role of CD8(+) T cells in human disease and could form the basis for a safe, highly selective therapy of autoimmune disorders. Major histocompatibility complex (MHC) tetramers (multimeric complexes capable of binding to specific CD8 T-cell clones) were conjugated to (225)Ac (an alpha-emitting atomic nanogenerator, capable of single-hit killing from the cell surface) to create an agent for CD8 T-cell clonal deletion. The "suicide" tetramers specifically bound to, killed, and reduced the function of their cognate CD8 T cells (either human anti-Epstein-Barr virus (EBV) or mouse anti-Listeria in 2 model systems) while leaving the nonspecific control CD8 T-cell populations unharmed. Such an approach may allow a pathway to selective ablation of pathogenic T-cell clones ex vivo or in vivo without disturbing general immune function.
Prime-boost immunization is a promising strategy for inducing and amplifying pathogen- or tumor-specific memory CD8 T cell responses. Although expansion of CD8 T cell populations following the second Ag dose is integral to the prime-boost strategy, it remains unclear when, after priming, memory T cells become competent to proliferate. In this study, we show that Ag-specific CD8 T cells with the capacity to undergo extensive expansion are already present at the peak of the primary immune response in mice. These early memory T cells represent a small fraction of the primary immune response and, at early time points, their potential to proliferate is obscured by large effector T cell populations that rapidly clear Ag upon reimmunization. With sufficient Ag boosting, however, secondary expansion of these memory cells can be induced as early as 5-7 days following primary immunization. Importantly, both early and delayed boosting result in similar levels of protective immunity to subsequent pathogen challenge. Early commitment and differentiation of memory T cells during primary immunization suggest that a short duration between priming and boosting is feasible, providing potential logistic advantages for large-scale prime-boost vaccination of human populations.
This study investigated the potential of human skeletal myoblast carrying human VEGF(165) for angiomyogenesis for cardiac repair. A porcine heart model of chronic infarction was created in 18 female swine by coronary artery ligation. The animals were randomized into: group 1, DMEM injected ( n=6), group 2, myoblast transplanted ( n=5) and group 3, VEGF(165) myoblast transplanted ( n=7). Three weeks later 5 ml DMEM containing 3x10(8) myoblast carrying exogenous genes were injected into 20 sites in left ventricle intramyocardially in groups 2 and 3. Group 1 animals were injected 5 ml DMEM without cells. Animals were kept on 5 mg/kg cyclosporine per day for 6 weeks. Regional blood flow was measured using fluorescent microspheres. The heart was explanted between 6-12 weeks after transplantation for histological studies. Histological examination showed survival of lac-z expressing myoblasts in host tissue. Capillary density at low power field (x100) was 57.13+/-4.20 in group 3 which was significantly higher than the other groups. Regional blood flow was significantly improved 6 and 12 weeks after transplantation, which was 2.41+/-0.11 and 3.39+/-0.11 ml(-1) min(-1) g(-1), respectively, in group 3. Left ventricular ejection fraction increased from 31.25+/-4.09% to 43.0+/-2.68% at 6 weeks in group 3. Human myoblasts are potential transgene carriers for the myocardium, in addition to strengthening the weakened myocardium through myogenesis.
Transient TCR stimulation induces multiple rounds of CD8 T cell division without further requirement for Ag. The mechanism driving Ag-independent proliferation, however, remains unclear. In this study, we show that the initial duration of TCR stimulation positively correlates with the number of divisions that CD8 T cells subsequently undergo. We find that increased periods of Ag stimulation result in enhanced CD25 up-regulation and greater IL-2 production by CD8 T cells. Depletion of IL-2 from T cell cultures with specific Abs dramatically impairs programmed proliferation. Consistent with this result, IL-2-deficient T cells undergo markedly attenuated Ag-independent proliferation in vitro. Although IL-2 production by stimulated CD8 T cells appears to be essential for in vitro proliferation, upon transfer into recipient mice, IL-2-deficient CD8 T cells undergo extensive proliferation in vivo after transient stimulation. Furthermore, the extent of in vivo proliferation correlates with the duration of in vitro Ag stimulation. These results indicate that the requirements for autocrine IL-2 production by CD8 T cells differs between in vitro and in vivo conditions and suggests that factors in addition to IL-2 can support Ag-independent CD8 T cell proliferation.
MHC class I-restricted antigen presentation is an essential step in the priming of CD8 T lymphocytes during immune responses to infection. While microbial growth and clearance have been accurately measured in mammalian hosts, the duration of functional antigen presentation during infection remains undefined in vivo. Herein we characterize the activation of naive and memory T cells at different times during bacterial infection. Surprisingly, the host's ability to prime T cells is of much shorter duration than bacterial infection, inversely correlating with the development of pathogen-specific cytolytic T lymphocytes. Our studies demonstrate a feedback mechanism that limits the duration of effective in vivo antigen presentation, thereby modulating T cell responses by temporally restricting recruitment of naive T cells into the immune response.
AIM: The aim of this study was to audit the efficacy of endoscopic injection therapy for non-variceal upper gastrointestinal (GI) bleeding at Auckland Hospital. METHODS: The medical records of 183 patients who had undergone endoscopic injection of adrenaline for non-variceal upper GI bleeding at Auckland Hospital between November 1996 and May 1999 were reviewed. RESULTS: Primary haemostasis was achieved in 177 (96.7%) patients and six (3.3%) patients had early surgery due to failure of injection therapy. The overall rate of rebleeding was 18.6%. The rate of rebleeding according to the stigmata seen at the time of endoscopy was 36.8% for patients showing spurting vessel; 24% for active ooze; 18.2% for visible vessel; and 3.2% for adherent clot. Active spurting vessels seen on endoscopy were associated with higher risk of repeat injection (p <0.01) and death (p <0.001). Sixteen (9%) patients had repeat injection. Haemostasis was achieved in all, and no deaths or surgical interventions were observed in this subgroup. CONCLUSIONS: Endoscopic injection therapy is an effective, simple and cheap first-line therapy for non-variceal upper GI bleeding. The repeat injection also appears to be an effective treatment for patients rebleeding after the initial injection therapy.
Coronary stents have been the major advancement in percutaneous coronary intervention in the last decade and are used in 60% to 80% of patients. However, in-stent restenosis continues to be a problem, occurring in 20% to 30% of cases. The clinical presentation of patients who develop restenosis after stenting has not been well characterized. In this study we compared the clinical presentation of in-stent restenosis with that of restenosis without stenting. Of 739 patients who underwent percutaneous coronary intervention and had repeat catheterization between October 1, 1997, and June 30, 2000, 262 consecutive patients with recurrent ischemia and restenosis were identified: 191 patients with (group A) and 71 without (Group B) stenting. Patients who underwent interventions in bypass grafts and those who developed early acute stent thrombosis were excluded from the study. Recurrent clinical ischemia occurred at a mean of 5.5 months in group A and 6.5 months in group B (p = 0.24). Rest angina (Braunwald class II and III) was more frequent in group A (48% vs 32%, p = 0.032). Acute coronary syndromes, the combination of rest angina, and acute myocardial infarction were also more frequent in group A (68% vs 46%, p = 0.03). Patients in group A were more likely to have angiographically visible thrombus than those in group B (9% vs 0%, p = 0.02). Thus, acute coronary syndromes are a common clinical presentation of restenosis among patients whose follow-up angiogram is obtained for clinical reasons, and occur more frequently in patients with in-stent restenosis than in those with restenosis without stenting.
Cytotoxic T lymphocytes (CTL) respond to antigenic peptides presented on MHC class I molecules. On most cells, these peptides are exclusively of endogenous, cytosolic origin. Bone marrow-derived antigen-presenting cells, however, harbor a unique pathway for MHC I presentation of exogenous antigens. This mechanism permits cross-presentation of pathogen-infected cells and the priming of CTL responses against intracellular microbial infections. Here, we report a novel diphtheria toxin-based system that allows the inducible, short-term ablation of dendritic cells (DC) in vivo. We show that in vivo DC are required to cross-prime CTL precursors. Our results thus define a unique in vivo role of DC, i.e., the sensitization of the immune system for cell-associated antigens. DC-depleted mice fail to mount CTL responses to infection with the intracellular bacterium Listeria monocytogenes and the rodent malaria parasite Plasmodium yoelii.
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CD8 T cells respond to viral infections but also participate in defense against bacterial and protozoal infections. In the last few years, as new methods to accurately quantify and characterize pathogen-specific CD8 T cells have become available, our understanding of in vivo T cell responses has increased dramatically. Pathogen-specific T cells, once thought to be quite rare following infection, are now known to be present at very high frequencies, particularly in peripheral, nonlymphoid tissues. With the ability to visualize in vivo CD8 T cell responses has come the recognition that T cell expansion is programmed and, to a great extent, independent of antigen concentrations. Comparison of CD8 T cell responses to different pathogens also highlights the intricate relationship between microbially induced innate inflammatory responses and the kinetics, magnitude, and character of long-term T cell responses. This review describes recent progress in some of the major murine models of CD8 T cell-mediated immunity to viral, bacterial, and protozoal infection.