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Biomedical subjects

R D Forbes

Publications and source records attributed to R D Forbes.

At least 37 records · Page 2Linked to original sources
PubMed1989

CD4+/Leu-7+ large granular lymphocytes in long-term renal allograft recipients. A subset of atypical T cells.

In long-term renal allograft recipients on conventional immunosuppression, we have previously reported an abnormal expansion of CD3+/Leu-7+ cells. These cells are large granular lymphocytes without any natural killer activity. About 20% of these CD3+/Leu-7+ cells coexpress the CD4 differentiation antigen. In 65 transplant recipients at risk for more than 6 months, the mean percentage of peripheral blood CD4+/Leu-7+ cells is significantly increased compared with 34 normals (5.0 +/- 0.6% versus 1.0 +/- 0.1%, P less than 0.0001). Patients who never received azathioprine do not show such an abnormality. We carried out this study to further define the phenotype, morphology, and function of these cells. As to phenotype, they coexpress CD2, CD3 but do not coexpress CD1, CD8, CD11, CD16, CD19, CD25, HLA-DR, Leu-M3. Morphologically, CD4+/Leu-7+ cells are typical large granular lymphocytes undistinguishable from CD16+ effector NK cells. CD4+/Leu-7+ cells do not exhibit any natural killer cell activity. In contrast to CD4+/Leu-7- cells, CD4+/Leu-7+ cells do not proliferate when stimulated with either lectins (Con A, PHA) or allogeneic cells. When stimulated for 3 days with PHA, sorted CD4+/Leu-7+ cells do not express IL-2 receptors as detected with a PE-conjugated anti-CD25 monoclonal antibody, whereas 40% of CD4+-Leu-7- cells do so. Finally, when stimulated with PHA, CD4+-Leu-7+ cells are not able to produce detectable levels of IL-2, while CD4+-Leu-7- cells do so. In long-term renal allograft recipients on conventional immunosuppression, Leu-7 antigen identifies a subset of CD4+ cells that do not behave like regular T helper cells. We speculate that these cells represent an alteration in the cellular environment in transplant recipients, perhaps leading to long-term complications such as cancers and chronic viral infections.

Adult↗
PubMed1989

Internal carotid artery aneurysm and Marfan's syndrome.

Aneurysms of the extracranial carotid artery are most commonly caused by atherosclerosis or trauma but may also have unusual causes, such as Marfan's syndrome. Although aneurysmal changes in the extracranial carotid vessels usually are due to extension of aortic dissection into the carotid system, isolated aneurysms may occasionally complicate Marfan's syndrome. The authors report a case of Marfan's syndrome in which the patient, a 45-year-old woman, presented with an asymptomatic mass in the right side of the neck at the level of the carotid bifurcation. An isolated internal carotid artery aneurysm was identified. The aneurysm was resected using an interposition vein graft over an outlying shunt. Histologic examination confirmed the typical cystic medial necrosis with loss of elastic fibres and an increase of mucoid material in the media. The patient's recovery was smooth and at 2-year follow-up there were no signs of recurrent aneurysm formation.

Aneurysm↗
PubMed1988

Immune mechanisms and molecular mediators of glomerular injury in experimental nephritis. Summary of current results and continuing studies.

Despite a growing body of evidence on the importance of macrophage accumulation in renal glomeruli to the subsequent injury in experimental immune nephritis, exact mechanisms of the monocyte/macrophage recruitment and phenomena leading to tissue damage are not completely clarified. Our experiments indicate that neutral proteinases released in situ by activated macrophages may, at least in part, be responsible for the development of autoimmune nephrotoxic glomerulonephritis in rats. Accordingly, apart from the well-established features of glomerular hypercellularity and basement membrane damage, a new mechanism of direct cytolysis by macrophage-derived proteinases is postulated to be of potential relevance to the nephritic glomerular injury.

Animals↗
PubMed1988

Morphologic studies of acute rat cardiac allograft rejection across an isolated major histocompatibility complex class I (RT1A) disparity.

To define the morphologic correlates of acute rat cardiac allograft rejection across an isolated major histocompatibility complex (MHC) class I disparity, rejecting PVG.R1 cardiac allografts transplanted to (PVG x WF)F1 recipients were studied from days 4-8 posttransplantation. Documented ultrastructural tracer techniques as well as immunohistologic and immunoelectron microscopic methods were employed for morphologic analysis. Using intravenously administered horseradish peroxidase as a tracer probe for cell membrane permeability dysfunction, it was shown that severe diffuse loss of integrity of the microvascular endothelium preceded functional rejection, providing strong evidence that the allograft microcirculation is a central target of graft destruction. Also, rejection was associated with localized cardiac myofiber alterations prior to development of significant endothelial changes, indicating that cardiac muscle cells are additional cellular targets of immunologic injury. The ultrastructural features of progressive endothelial and myofiber injury, the predominance of MRC OX8+ lymphocytes and MRC OX6+ macrophages sequestered within the grafts, and the pattern of donor class I expression by allograft endothelium and cardiac myofibers were similar to those observed in rejecting allografts in full MHC-disparate combinations. Since it has been previously shown that MRC OX8+ class I-reactive T cells are absolutely required for rejection in this isolated class I-disparate model, the morphologic data raise the possibility that the OX8+ T lymphocyte subpopulation may also play a highly significant role in rat cardiac allograft rejection across a full MHC disparity.

Animals↗
PubMed1986

Dendritic cell-lymphoid cell aggregation and major histocompatibility antigen expression during rat cardiac allograft rejection.

To determine the pattern of cellular expression of donor MHC class I and class II antigens during the course of rat cardiac allograft rejection, ACI cardiac allografts transplanted to BN recipients were examined from day 2 to day 6 using immunohistologic and immunoelectron microscopic methods. We used both monomorphic and donor-specific mouse anti-rat MHC class I and class II mAbs in this study. In normal ACI hearts, MHC class I reactivity was confined to the vascular endothelium and to interstitial cells. Ongoing rejection was characterized by an increased donor MHC class I staining intensity of microvascular endothelium and induction of donor class I surface reactivity on cardiac myofibers. Donor MHC class II reactivity was exclusively confined to interstitial dendritic cells (IDC) in both normal ACI hearts and in rejecting allografts, although rejection was associated with marked fluctuations in class II IDC frequency. An early numerical depression in class II IDC present in both allografts and syngeneic heart grafts was attributed to a direct effect of the transplantation procedure. By days 3-4, allografts showed an absolute overall increase in donor class II IDC frequency, which was associated with the presence of multiple localized high-density IDC-lymphocyte aggregates. The lymphocytes present in the focal areas were predominantly of the class II-reactive Th cell subpopulation. These aggregates may thus represent the in vivo homologue of dendritic cell-lymphocyte clustering, which has been shown to be required for primary class II allosensitization in the rat and mouse in vitro. During the late phase of rejection, there was a marked numerical fall in donor class II IDC, which correlated with extensive overall graft destruction. This study has shown that acute rat cardiac allograft rejection can occur in the absence of donor MHC class II expression by allograft vascular endothelium and cardiac myofibers. The IDC, which are believed to represent the principal class II alloantigen presenting cells in the rat heart, remain the sole class II-expressing cellular constituents of the graft throughout the course of rejection.

Animals↗
PubMed1986

Reduction of azathioprine in renal transplant patients with chronic hepatitis.

To determine whether prolonged reduction of azathioprine in renal transplant recipients with chronic hepatitis affected the progression of liver disease without an adverse effect on graft survival we studied all transplant patients with a raised serum glutamic oxaloacetic transaminase level greater than normal for more than 1 year who had azathioprine reduced below 100 mg/day for longer than 1 year. Six HBsAg-positive patients had chronic hepatitis for 67 +/- 7 (SE) months before reduction of azathioprine and were followed for a further 49 +/- 14 months. None of the six patients remitted, 3 patients died from liver disease, and none returned to dialysis. In the group of 12 patients who did not have azathioprine reduced, none remitted, 4 died from liver disease, and none returned to dialysis during a follow-up of 115 +/- 9 months. Seven HBsAG-negative patients had chronic hepatitis for 32 +/- 11 months before reduction of azathioprine and were followed for a further 46 +/- 8 months. One of the seven remitted, none died from liver disease and one returned to dialysis. In the group of 15 patients who did not have azathioprine reduced 5 patients remitted, none died from liver disease, and none returned to dialysis. We conclude that prolonged reduction of azathioprine does not slow the progression of liver disease in renal transplant recipients with HBsAg-positive or HBsAg-negative chronic hepatitis, nor does it predispose to graft failure. However reduction of immunosuppression early in the course of hepatitis B disease may be necessary to prevent adverse long-term sequelae.

Adult↗
PubMed1985

Chronic hepatitis in end-stage renal disease: comparison of HBsAg-negative and HBsAg-positive patients.

To determine the outcome of chronic hepatitis in ESRD we studied all 358 renal transplant recipients and 295 hemodialysis patients treated for greater than 1 year since 1970. The incidence of chronic hepatitis (elevated SGOT for greater than 1 year) was 15% (N = 54) in transplanted and 3.4% (N = 10) in dialysis patients. Forty-eight percent (26) of transplanted and 50% (5) of dialysis patients were HBsAg positive. In the transplanted group, the clinical outcome of chronic hepatitis was significantly better in HBsAg-negative compared to HBsAg-positive patients; 11% died, none from liver disease, and 32% remitted after a mean follow-up from start of liver disease of 77.3 +/- 8.2 months, whereas in the HBsAg-positive group 54% (14) died, nine from liver disease, and one remitted after a follow-up of 90.2 +/- 8.9 months. Adverse prognostic factors (age, duration of diabetes, and heart disease) present before ESRD treatment began were similar in both groups, as was duration of follow-up. Only 14% (2/14) of HBsAg-negative patients progressed to chronic active hepatitis on liver biopsy compared to 71% (15/21) of HBsAg-positive patients. Histological stability in those with serial biopsies occurred in 66% (4/6) of HBsAg-negative patients, but in only 18% (13/16) of HBsAg-positive patients with a similar duration of follow-up. No dialysis patients died from liver disease. We conclude that chronic hepatitis occurs more frequently in transplanted than dialyzed patients, and that HBsAg-negative chronic hepatitis has a more benign, clinical, and histological outcome than chronic HBsAg-positive hepatitis in renal transplant recipients.

Female↗
PubMed1985

The impact of renal transplantation on the course of hepatitis B liver disease.

To establish the impact of transplantation on the course of chronic hepatitis B liver disease we performed a prospective study of the clinical and pathological sequelae of hepatitis B disease in all 22 patients who had renal allografts that functioned for more than 1 year and who were hepatitis B surface antigen (HBsAg)-positive following transplantation. No patient converted to HBsAg-negative. During a mean follow-up of 83 months serial liver biopsies were performed in 20 patients and 1 liver biopsy was available in the remaining 2 patients. Eleven patients died of liver disease, 5 of whom died of hepatic failure, 3 with hepatoma, 2 of gastrointestinal hemorrhage, and 1 of ascites with pleuroperitoneal fistula. Aggressive liver disease was observed in the vast majority of patients: 12 ultimately developed cirrhosis, (mean follow-up 81 months), 6 chronic active hepatitis (mean follow-up 93 months), 3 chronic persistent hepatitis (mean follow-up 89 months), and in 1 patient the presence of HB virus in hepatocytes was the sole morphologic alteration (follow-up 42 months). There was a marked tendency to progression in that 82% of patients with virus only, reactive hepatitis, or chronic persistent hepatitis on initial biopsy subsequently developed chronic active hepatitis or cirrhosis. For comparison, 10 HBsAg-positive patients whose renal failure had been treated by hemodialysis were also studied over a comparable period. Four patients converted to the negative state. Biochemical evidence of persistent liver dysfunction occurred in only 1 patient and no patient has died from complications of liver disease. We conclude that in the immunosuppressed renal transplant patient HB infection often results in the development of cirrhosis, leading to death from hepatoma and hepatic failure. This course is worse than that in dialysis patients. Renal transplantation of HBsAg-positive patients with end-stage renal failure may be inadvisable.

Aspartate Aminotransferases↗
PubMed1985

Comparative immunohistologic studies in an adoptive transfer model of acute rat cardiac allograft rejection.

It has been shown that fulminant acute rejection of rat cardiac allografts across a full haplotype disparity may occur as a direct result of adoptive transfer of sensitized W3/25+ MRC OX8- SIg- T helper/DTH syngeneic spleen cells to sublethally irradiated recipients. In order to establish the immunohistologic parameters of this form of rejection, allografts and recipient lymphoid tissue were analyzed using a panel of monoclonal antibodies of known cellular distribution. These data were compared with those obtained following reconstitution of irradiated allograft recipients with unseparated sensitized spleen cells, with unreconstituted irradiated donor recipient pairs, with unmodified first-set rejection, and with induced myocardial infarction of syngeneic heart grafts transplanted to normal and to sublethally irradiated recipients. Rejecting cardiac allografts transplanted to all reconstituted irradiated recipients were characterized by extensive infiltration with MRC OX8+ (T cytotoxic-suppressor, natural killer) cells even when this subset was virtually excluded from the reconstituting inocula. A similar proportional accumulation of MRC OX8+ cells observed at the infarct margins of syngeneic heart grafts transplanted to irradiated unreconstituted recipients greatly exceeded that present in normal nonirradiated controls. These data provide evidence that under conditions of heavy recipient irradiation, MRC OX8+ cells may be sequestered within heart grafts in response to nonspecific injury unrelated to the rejection process. Although there was no significant degree of MRC OX8+ cellular repopulation within organized secondary lymphoid tissues of irradiated animals over the study period, the density of ileal mucosal MRC OX8+ lymphocytes approximated normal at 7 days post-irradiation, raising the possibility that these cells could share a common origin with those sequestered within the heart grafts. Carbon+ MRC OX6+ macrophages were a significant component of the infiltrate in all rejecting cardiac allografts, as well as in all infarcted syngeneic heart grafts--providing further evidence that macrophage "activation" with expression of class II determinants may occur in response to nonspecific injury. In unmodified first-set rejection there was an intense B cell reaction in recipient spleens and lymph nodes. In the adoptive transfer model, marked B cell expansion was exclusively confined to the parathymic lymph nodes of irradiated allograft recipients reconstituted with the sensitized W3/25+, MRC OX8-, SIg- T helper/DTH donor cell inocula.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Immune mechanisms in organ allograft rejection. V. Pivotal role of the cytotoxic-suppressor T cell subset in the rejection of heart grafts bearing isolated class I disparities in the inbred rat.

The cellular requirements for rejection of heart grafts bearing isolated major histocompatibility complex (MHC) subregion RT1A-encoded class I disparities was assessed by adoptive transfer. Sublethally irradiated (780 rads) (PVG X WF)F1 recipients of irradiated PVG-RT1r1 heart grafts were selectively reconstituted with spleen cells from syngeneic donors previously sensitized with two sequential PVG-RT1r1 skin grafts. PVG-RT1r1 heart grafts were rejected acutely in recipients reconstituted with 10 X 10(6) unfractionated immune spleen cells (7-9 days, n = 6) or inocula (5 X 10(6) cells) depleted of SIg+ cells (10-13 days, n = 5), but additional depletion of cytotoxic T cells and their precursors (OX8+) resulted in marked prolongation of graft survival (n = 4, 4 X 10(6) cells, 45-67 days). Reducing the reconstituting inocula from 4 X 10(6) to 2.5 X 10(6) spleen cells (OX8-, SIg-) prolonged graft survival to that observed in unreconstituted recipients (generally greater than 100 days). Additional studies were performed to define the immunologic basis for prolonged survival of PVG-RT1r1 heart grafts in homozygous PVG recipients. Although lymphoid cells of naive PVG failed to proliferate (stimulation index [SI] 1.01, P = NS) on coculture with irradiated PVG-RT1r1, bulk cultures yielding but weak and variable CTL generation, lymphoid cells from specifically sensitized PVG proliferated (SI 4.25, P less than .001) and generated greater cytotoxic T lymphocyte (CTL) activity (P less than .001) under identical conditions, strongly suggesting, therefore, that prolonged heart graft survival in this strain combination is related to low CTL precursor frequency. Further, though PVG-RT1r1 heart grafts were rejected in 10-12 days (n = 3) by (PVG X WF)F1 recipients, (PVG-RT1r1 X WF)F1----(PVG X WF)F1 heart grafts (RT1Aa disparity) survived greater than 100 days despite an equivalent alloimmune response, and this was shown to correlate with a reduced sensitivity of (PVG-RT1r1 X WF)F1 target cells to lysis by CTL. These data, therefore, strongly suggest that the pivotal role of CTL in the rejection of class-I-disparate heart grafts is, in fact, related to their function in direct cell-mediated cytolysis.

Animals↗
PubMed1984

The nonessential role of a humoral antibody response in acute rat cardiac allograft rejection. An ultrastructural tracer study in an adoptive transfer model.

Progressive microvascular endothelial damage is a characteristic feature of fulminant acute cardiac allograft rejection in the rat. Serial ultrastructural tracer studies using i.v. administered colloidal carbon and horseradish peroxidase have been performed in an adoptive transfer model to determine the role of cellular and humoral immune mechanisms in the pathogenesis of endothelial injury in this setting. Sublethally irradiated (780 rads) Lewis recipients of Wistar-Furth cardiac allografts reconstituted with unfractionated syngeneic immune spleen cells (2 X 10(7)] or with inocula depleted of SIg+ cells (1 X 10(7)] were studied at days 5-7 posttransplantation, and the ultrastructural tracer data were correlated with recipient alloantibody titers. The progression of microcirculatory endothelial damage within rejecting cardiac allografts was similar when recipients were reconstituted with unfractionated immune spleen cells or with SIg- cells, and the serial changes present were comparable to those documented in unmodified first-set rejection in this strain combination. Unreconstituted controls showed no apparent microvascular alterations. A significant alloantibody response was confined to recipients reconstituted with unfractionated immune spleen cells. All unreconstituted recipients and recipients that received splenic inocula depleted of SIg+ cells (SIg-) lacked detectable antibody in the study period. These results indicate that a humoral antibody response is not essential for induction of endothelial damage in fulminant acute rejection of rat cardiac allografts.

Acute Disease↗