Tumour infiltrating lymphocytes: insights into tumour immunology and potential therapeutic implications.
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Journal Article↗
Biomedical subjects
D H Adams
Publications and source records attributed to D H Adams.
Reduced mortality and morbidity for ascending aortic aneurysm resection regardless of cause.
BACKGROUND: This study was done to answer the question, "What is the current risk of resection of ascending aortic aneurysms regardless of acuity or cause?" METHODS: One hundred fifteen consecutive patients who underwent ascending aortic aneurysm repair from January 1, 1990, to July 1, 1995, were retrospectively reviewed, excluding those with acute ascending aortic dissection. The mean age was 59 years; 55% were male. Concomitant procedures included coronary artery bypass in 23 (20%) and arch repair in 12 (10%). In group 1, 54 patients had replacement of the aortic valve, root, and ascending aorta with a valve-graft conduit using the "Bentall" technique, and of these 19 (35%) had Marfan's syndrome. In group II, 44 patients had separate aortic valve repair or replacement and supracoronary ascending aortic replacement. In group III, 17 patients had supracoronary ascending aortic replacement, without aortic valve operation. Operative techniques included frequent use of (1) intraoperative transesophageal echocardiography or epiaortic ultrasound scanning of the ascending and descending thoracic aorta to help guide arterial cannulation, avoid atherosclerotic embolization, and assess the repair; (2) antegrade and retrograde multidose cold blood cardioplegia for myocardial protection; (3) exclusion and button anastomotic techniques to ensure secure suture lines; (4) antifibrinolytic agents and collagen-impregnated aortic grafts to reduce bleeding; and (5) deep hypothermic circulatory arrest and the open distal anastomotic technique in patients with distal ascending and arch aortic disease. RESULTS: Operative mortality overall was 2/115 (1.7%). Mortality was 1/54 (1.8) in group I and 1/44 (2%) in group II, and there was no mortality in group III. The overall postoperative morbidity was 3% due to bleeding, 2% due to stroke, and 1% due to myocardial infarction. The length of stay in the past year has decreased to less than 7 days. CONCLUSIONS: The current risk for ascending aortic aneurysm repair is low (< 2%) whether or not the aortic root or valve also needs repair, regardless of the cause of the aneurysm.
Adult↗
Determinants of early mortality and late survival in mitral valve endocarditis.
BACKGROUND: Infective mitral valve endocarditis continues to be a significant surgical challenge. The objective of this study was to examine our experience with mitral valve endocarditis surgery and identify determinants of early mortality and late survival. METHODS AND RESULTS: Over a 24-year period, mitral valve surgery was performed in 96 patients for infective mitral valve endocarditis. Patient age ranged from 20 to 78 years (median age, 52 years). There were 44 women (46%), and 48 of the 96 patients (50%) were in New York Heart Association functional class IV before surgery. Native valve endocarditis (NVE) and prosthetic valve endocarditis (PVE) were present in 72 patients (75%) and 24 patients (25%), respectively. Surgery during the active phase of endocarditis (AE) was required in 60 patients (62%) and during the healed phase (HE) in 36 (38%). The main indications for surgery in the AE group were congestive heart failure (60%), active sepsis (67%), peripheral emboli (47%), and acute renal failure (20%), and for the HE group the main indication was progressive congestive heart failure (69%). The overall operative mortality was 5.2%. Multivariate logistic regression analysis identified PVE (odds ratio [OR] 22.5; +/- 95% confidence interval, CI, 1.9 to 268; P = .014) and an associated procedure (OR 13.3; +/- 95% CI, 1.5 to 120; P = .021) to be independent predictors for early mortality. Follow-up was 97% complete, with a median of 3.5 years. Overall 5- and 10-year survivals were 83 +/- 4% and 63 +/- 8%, respectively. Multivariate analysis for late mortality identified PVE to be a significant predictor of late mortality (hazards ratio = 3.1, +/- 95% CI, 1.4 to 6.8, P = .006). There were no significant differences in long-term morbidity results among the various subsets of mitral valve endocarditis. CONCLUSIONS: Mitral valve surgery for infective endocarditis is a significant high-risk procedure for PVE and when combined with associated procedures. The activity of endocarditis does not appear to have any influence on early mortality or long-term survival.
Adult↗
Intrathymic tolerance in the Lewis-to-F344 chronic cardiac allograft rejection model.
Successful induction of donor-specific unresponsiveness by intrathymic inoculation of alloantigen in several experimental acute rejection models has led us to hypothesize that similar immune manipulations can prevent chronic rejection and development of graft arteriosclerosis in the Lewis-to-F344 rat chronic cardiac allograft rejection model. Recipient F344 rats were treated with donor (Lewis) splenocytes by intrathymic injection (i.t.) alone (10 x 10(6) cells/lobe); with donor splenocytes i.t. plus a one-time dose of ALS (1 mg) by intraperitoneal injection (i.p.); or with ALS i.p. (1 mg) alone 2 and 6 weeks prior to heterotopic Lewis heart transplantation. Control F344 recipients received saline i.t. Allografts were monitored by daily palpation, and long-term surviving grafts were harvested on day 90 for histopathologic analysis. Control allografts had 28.6% long-term survival (> 90 days) with mean graft survival of 46.7 +/- 12.2 days. At day 90 the surviving control allografts were enlarged and fibrotic with barely palpable heartbeat (mean heartbeat grade 0.29 +/- 0.18), and histologically showed diffuse moderate mononuclear cell infiltrates and advanced graft arteriosclerosis (mean vessel score 3.57 +/- 0.10 and 89 +/- 1% vessels diseased). Recipient treatment with intrathymic donor splenocytes alone significantly prolonged graft survival (89% long-term survival; mean 83.8 +/- 6.2 days, P < 0.04), but did not significantly inhibit the development of graft arteriosclerosis (score 2.98 +/- 0.53 and 79 +/- 8% diseased, P = NS). By contrast, treatment with i.t. donor splenocytes plus ALS 2 weeks prior to transplantation prolonged graft survival (100% long-term; mean 90.0 +/- 0.0 days, P < 0.04), and markedly inhibited graft arteriosclerosis (score 0.80 +/- 0.14, P < 0.05; 27 +/- 4% diseased, P < 0.05). ALS alone given two weeks prior to transplantation also prolonged graft survival (100% long-term; mean 90.0 +/- 0.0 days, P < 0.04), and inhibited graft arteriosclerosis (score 0.89 +/- 0.31, P < 0.05; 25 +/- 7% diseased, P < 0.05). However, when ALS was given 6 weeks prior to heart transplantation the beneficial effect of ALS alone was abolished, suggesting that lymphocyte depletion may have been responsible for the observed effects when ALS was administered at 2 weeks. Interestingly, intrathymic donor splenocytes plus ALS 6 weeks prior to transplantation, on the other hand, showed significant prolongation of allograft survival (100% long-term, mean 90.0 +/- 0.0 days, P < 0.04), and inhibited graft arteriosclerosis (score 0.41 +/- 0.02, P < 0.05; 16 +/- 2% diseased, P < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Upregulation of cytokines associated with macrophage activation in the Lewis-to-F344 rat transplantation model of chronic cardiac rejection.
Lewis-to-F344 rat cardiac allografts develop chronic rejection and arteriosclerotic lesions rich in mononuclear cells (especially macrophages). This study was performed to determine whether cytokine pathways associated with macrophage activation are upregulated in hearts undergoing chronic rejection. Gene transcript levels for IFN-gamma, monocyte chemoattractant protein-1 (MCP-1), and IL-6 were measured with reverse-transcription PCR assays optimized for each gene. Gene products were confirmed by immunohistology. For all three genes, transcript levels in rat cardiac allografts increased significantly on day 7 and remained elevated on days 14 and 28 posttransplantation, as compared with naive hearts, paired host hearts, and syngrafts (P < 0.006). For the inducible genes IFN-gamma and MCP-1, high transcript levels in cardiac allografts were in contrast with low levels in host spleens. On the other hand, transcript levels for the basally expressed gene IL-6 were elevated in both organs. Immunostaining confirmed allograft-specific expression for all three cytokines and localized the gene products to infiltrating mononuclear cells in the interstitium and vasculature. The sustained expression of these cytokines in cardiac allografts undergoing chronic rejection supports the widely held hypothesis that the intimal changes associated with transplant arteriosclerosis are mediated by cellular activation and cytokine production.
Animals↗
Apoptosis in the human liver during allograft rejection and end-stage liver disease.
The contribution of apoptosis (programmed cell death) to cellular damage in human liver disease is unknown. Using the in situ DNA end labelling method (ISEL), evidence was sought of programmed cell death (PCD) in liver tissue from patients with various liver diseases. In particular, the study aimed to determine whether PCD is involved in either the loss of interlobular bile ducts (vanishing bile duct syndrome--VBDS) or the perivenular hepatocyte drop-out, both of which are characteristic of irreversible graft rejection. Large numbers of apoptotic hepatocytes were found in perivenular areas in tissues taken from patients with chronic graft rejection. Significant hepatocyte apoptosis, was not seen in long-term stable allografts, primary biliary cirrhosis, cholestasis, paracetamol-induced fulminant hepatic failure, or fulminant hepatic failure of indeterminate origin (non-A, non-B, non-C hepatitis). Bile ducts rarely stained positively, but mononuclear cells present in the post-transplant tissues were frequently positive, showing nuclear or cytoplasmic staining. The presence of cytoplasmic staining suggested that some mononuclear cells had ingested apoptotic DNA from other cellular sources. PCD may thus contribute to the perivenular hepatocyte loss in chronic rejection. The absence of ductular epithelial cell staining suggests that PCD is not involved significantly in the bile duct loss of VBDS. Furthermore, apoptosis of mononuclear cells implies that PCD may be involved in regulating the inflammatory cell infiltration of graft rejection.
Apoptosis↗
Adhesion molecules and liver transplantation: new strategies for therapeutic intervention.
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Animals↗
The 'infective' process in scrapie and human spongiform encephalopathy disease.
It is suggested that spongiform encephalopathy (SE) disease transmission does not occur by any classically defined 'infective' process. Rather, it is the case that conformationally altered prions in diseased animals are able, by targeting what may be an inherited, widely distributed, endogenous retroviral fragment, comprising the prion 'gene' system, to initiate the escalating synthesis of similar, but host-specified protein. Both initiation and the resulting progression are controlled and regulated by endogenous host genetic and other factors. While the prion system appears to be primarily involved, the intrinsic sequences of the invading prions also have a role in what appears to be a joint operation. A parallel may be drawn with EAE in that the disease is initiated by a small (myelin basic) protein, and in which, similarly, the ongoing process is host-specified, and regulated by genetic and other factors. The presence of polynucleotide in 'infective' inocula is probably unnecessary, if not irrelevant.
Animals↗
Triplet code-independent programming of living systems organisation by DNA: the link with intelligence and memory.
Previous suggestions from this laboratory (3), (a) that within its molecular electronic structure, DNA houses a computer-analog program of immense complexity, operating independently of, but complementary to, triplet coding and (b) that, inter alia, this program is the driving force for organising and executing the construction of species individuals in three dimensions, are extended in the present communication. It is now concluded that the DNA program also embodies an 'intelligence' component, which extends its organising ability both qualitatively and quantitatively beyond any of the heavily circumscribed 'self-organising' attributes claimed to be associated with naturally occurring inanimate systems. Further, that as part of the developmental process, a program component organises the fabrication of mammalian central nervous systems, including that of human beings with the associated attributes of intelligence, creativity and constructional skills. It is further suggested that the sophisticated random access memory system associated with human beings in particular may be explicable in terms of an extension of the DNA programming system: basically this involves the latter operating as computer-type 'hardware' for the storage of long-term memory and interacting with, primarily, glial cell RNA, acting as 'software' and storing short term traces. Finally, it is suggested that such an interrelationship between DNA/RNA molecular electronic structures can provide the necessary memory storage capacity and flexibility and also facilitates random access to the long-term DNA memory store.
Animals↗
The effect of pathophysiology on the surgical treatment of ischemic mitral regurgitation: operative and late risks of repair versus replacement.
Operative correction of ischemic mitral regurgitation (IMR) is associated with high risk approach. The objective of this retrospective study was to examine the interaction between the various underlying pathophysiologic mechanisms, the operative procedure, and their influence on short- and long-term outcomes. Over a 10-year period starting January 1984, mitral valve repair or replacement was performed on 150 patients with IMR. The age range was 42-86, mean 67, years; 71 (47%) were females; 139 (93%) were in NYHA functional class III or IV; 23 (15%) were reoperations; and 30 (20%) were in atrial fibrillation. Functional IMR due to annular dilatation or restrictive leaflet motion was present in 106 (71%), and structural IMR due to ruptured chordae or papillary muscle in 44 (29%). Mitral valve repair was performed in 94 (63%) with an annuloplasty ring employed in 80 (85%) patients. Mitral valve replacement was performed in 56 (37%), with 40 (71%) receiving a bioprosthesis (32 Hancock and 8 Carpentier-Edwards valves) and 16 (29%) a St. Jude valve. Coronary artery bypass graft surgery was performed in 139 (93%) patients. The overall operative mortality (OM) was 14/150 (9.3%). The OM for repair was 9.5% compared to 8.9% for replacement (P = NS). There was higher OM in the elderly, particularly in the repair group (P = 0.053), and a trend towards reduced OM in the recent years of the study (P = NS). No predictors of OM were identified by multivariate logistic regression analysis. Long-term follow-up was 98% complete and ranged from 2-120, mean 31.2, months for a total of 935 patient-years. The overall 5-year survival rate was 71 +/- 6%, with 91 +/- 5% for the replacement group compared to 56% +/- 10% for the repair group (P = 0.01). The functional subset of IMR who had a repair had the worse long-term survival (43 +/- 13%) compared to the structural/repair (76 +/- 13%) and structural/replacement groups (89 +/- 8%), and 92 +/- 7% for the functional/replacement group ((P = 0.0049). Multivariate logistic regression analysis identified the functional/repair group (hazards ratio 4.4; +/- 95%, confidence interval 1.6, 11, (P = 0.0031); and earlier years of surgery (hazards ratio 4.7; +/- 95% confidence interval 1.021; (P = 0.046) to be predictors of worse long-term survival. These results suggest that, in IMR, the underlying responsible pathophysiologic mechanisms appear to be the major determinants of survival, rather than the choice of the operative procedure.
Adult↗
Repair of mitral regurgitation from myxomatous degeneration in the patient with a severely calcified posterior annulus.
Severe posterior annular calcification poses a particular challenge to mitral valve repair. In a series of 252 mitral valve repairs for myxomatous degeneration performed between 1980 and 1993, 14 patients had a severely calcified posterior mitral valve annulus. Ages ranged from 61 to 81 years. Twelve patients were preoperative NYHA Class III or IV, and five patients required concurrent coronary artery bypass procedures. Operative techniques included complete resection of the calcified posterior annulus, resections of portions of the posterior leaflet with leaflet advancement, and placement of an annuloplasty ring. There were no operative deaths and all patients had a postoperative echocardiographic confirmation of relief from mitral regurgitation. During a mean follow-up time of 36 months (6 months to 8 years), there has been one late valve reoperation and only one late death, from thromboembolism in a patient with atrial fibrillation. These data indicate that even in the presence of severe calcification of the posterior mitral annulus, mitral valve repair for myxomatous degeneration can be performed with a low-operative risk and satisfactory long-term results.
Aged↗
Intrathymic injection of donor splenocytes plus systemic antilymphocyte serum or antilymphocyte serum alone prolongs cardiac allograft survival and inhibits graft arteriosclerosis in the Lewis-to-F344 chronic rejection model.
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Animals↗
Inhibition by FK506 of formyl peptide-induced neutrophil activation and associated protein synthesis.
The macrolide FK506 inhibited, by up to 50%, neutrophil migration and the production of the superoxide radical in response to the formyl peptide, formyl-methionyl-leucyl-phenylalanine (FMLP). The production of the superoxide radical in response to phorbol 12-myristate 13-acetate (PMA) was unaffected by FK506. The inhibition of neutrophil functions was accompanied by a partial reversal of FMLP-induced synthesis of cellular proteins, despite a rise in intracellular Ca2+. Neutrophils treated with FK506 demonstrated a small (average 23%) though significant decrease in formyl-peptide receptor numbers but receptor binding affinity was unaffected. The effects of FK506 on neutrophil activation appear to be analogous to those in T-lymphocytes. The incomplete inhibition, by FK506, of neutrophil responses suggests further that activation by FMLP is mediated via distinct multiple signalling pathways, including protein kinase activation and protein synthesis. The inability of FK506 to reduce FMLP-induced rises in cellular Ca2+ or PMA-induced activation of neutrophils suggests that its action is distal to Ca2+ mobilization and distinct from pathways relying on PKC activation. Thus the immunosuppressive effects of FK506 in vivo might be mediated through the inhibition of inflammatory cells other than lymphocytes and the drug therefore has therapeutic potential in a variety of inflammatory conditions. The drug also has potential in vitro for the characterization of signalling pathways from the plasma membrane to the nucleus.
Calcium↗
Hepatocyte growth factor and macrophage inflammatory protein 1 beta: structurally distinct cytokines that induce rapid cytoskeletal changes and subset-preferential migration in T cells.
T-cell migration into tissue depends on a cascade of rapid and selective adhesive interactions with endothelium. "Triggering" is a step in that cascade required to activate T-cell integrins. Hepatocyte growth factor (HGF) may be a physiologically relevant trigger, since we demonstrate that HGF can induce both adhesion and migration of human T-cell subsets and can be detected immunohistochemically on inflamed endothelium. HGF preferentially induces responses from T cells of memory phenotype, in contrast to macrophage inflammatory protein 1 beta (MIP-1 beta), a chemokine which acts preferentially on naive cells. HGF, like the chemokines, binds to heparin, and HGF retained in extracellular matrix is efficient in promoting migration. Further, both MIP-1 beta and HGF induce actin polymerization within seconds, kinetics that approach those required to contribute to physiologic triggering. HGF is a member of a structural family distinct from the chemokines, whose only known receptor is the tyrosine kinase c-Met. HGF induces tyrosine phosphorylation on T cells apparently via a distinct receptor, since no c-Met is detectable by surface staining, PCR, or anti-phosphotyrosine immunoprecipitation. Thus, promotion of T-cell adhesion and migration are previously undescribed functions of HGF that we propose are relevant to selective T-cell recruitment.
Cell Adhesion↗
Constitutive activation of integrin alpha 4 beta 1 defines a unique stage of human thymocyte development.
Our understanding of thymocyte development and of the positive and negative selection events involved in shaping the repertoire of mature T lymphocytes has been greatly facilitated by the use of transgenic and gene knockout animals. Much less is known about the factors that control the homing and population of the thymus by T cell precursors and the subsequent migration of developing thymocytes through the thymic architecture. As the integrins represent a candidate group of cell surface receptors that may regulate thymocyte development, we have analyzed the expression and function of alpha 4 beta 1 and alpha 5 beta 1 on human thymocytes. A major portion of double positive (CD4+ CD8+) human thymocytes express alpha 4 beta 1 in a constitutively active form and adhere to fibronectin and vascular cell adhesion molecule 1. alpha 4 beta 1 expression is similar on adherent and nonadherent populations, thus, activity reflects the receptor state and not simple expression. The adherent cells are immature, expressing high levels of CD4/CD8 and low levels of CD3 and CD69. In contrast, nonadherent cells possess the phenotype of thymocytes after positive selection, expressing intermediate levels of CD4 and/or CD8 and high levels of CD3 and CD69. The adherent population fails to respond to activation with anti-CD3 and fibronectin, whereas nonadherents exhibit an alpha 5 beta 1-dependent proliferation. Differential regulation of alpha 4 beta 1 and alpha 5 beta 1 receptors may provide a mechanism controlling cellular traffic, differentiation, and positive selection of thymocytes.
Antibodies↗
Leucocyte-endothelial interactions and regulation of leucocyte migration.
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Cell Adhesion↗
Endothelial activation and circulating vascular adhesion molecules in alcoholic liver disease.
Alcoholic hepatitis is characterized by hepatocyte necrosis associated with infiltration of the liver parenchyma by neutrophils. The mechanisms responsible for recruiting neutrophils to the liver are unknown. We report high circulating levels and tissue expression of the endothelial adhesion molecule E-selectin in alcoholic hepatitis. Because expression of E-selectin is involved in neutrophil transmigration into inflamed tissue, it may play a crucial role in the recruitment of neutrophils to the liver in alcoholic hepatitis. By contrast, we detected high levels of vascular cell adhesion molecule-1, the endothelial counter-receptor for the lymphocyte adhesion molecule very late antigen-4, in alcoholic cirrhosis, which is associated with a predominantly mononuclear cell infiltrate. Both diseases were associated with high levels of circulating intercellular adhesion molecule-1, which is released by activated lymphocytes, providing further evidence of immune activation in alcoholic liver disease.
Cell Adhesion↗
Single-clamp technique: an important adjunct to myocardial and cerebral protection in coronary operations.
To determine the myocardial and cerebral protective properties of the single cross-clamp (group I; n = 160) versus the partial occluding clamp (group II; n = 150) technique for construction of the proximal anastomoses, a retrospective analysis of 310 patients operated on by the same surgeon was performed. Group I patients were older (median age, 70 versus 64 years; p < or = 0.0001), with 83 (52%), versus 41 (27%) in group II, 70 years and older (p < or = 0.0001). More group I patients were in New York Heart Association functional class IV (42 [26%] versus 22 [15%]; p = 0.008); more required preoperative balloon counterpulsation (35 [22%] versus 16 [11%]; p = 0.006); and more required emergent operation (20 [13%] versus 3 [2%]; p < or = 0.0001). Antegrade crystalloid cardioplegia was used in both groups. The median cross-clamp time was 58 minutes for group I versus 44 minutes for group II (p < or = 0.0001). However, there was no significant difference between the two groups in terms of the number of bypass grafts, the use of the mammary artery, or the bypass time. The operative mortality was 2.5% (n = 4) for group I versus 5.3% (n = 8) for group II (p = 0.16), and the perioperative myocardial infarction/low cardiac output state was seen in 6 patients (3.8%) in group I versus 18 patients (12%) in group II (p = 0.006). The median creatine kinase MB release was 13 U/L for group I versus 19 U/L for group II (p = 0.0029).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗