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R D Forbes

Publications and source records attributed to R D Forbes.

At least 55 records · Page 3Linked to original sources

The clinical and pathological course of hepatitis B liver disease in renal transplant recipients.

A prospective study of the clinical and pathological sequelae of hepatitis B disease in 22 immunosuppressed renal transplant patients is reported. All patients had allografts that functioned for more than 1 year, and all were hepatitis B surface antigen (HBsAg)-positive following transplantation. None of the 18 patients who had serial HBsAg tests converted to HBsAg negative. Serial liver biopsies were performed in 19 patients and one liver biopsy was available in the remaining three patients. Follow-up ranged from 12 to 93 months. Seven patients ultimately developed cirrhosis, 6 developed chronic active hepatitis, 5 developed chronic persistent hepatitis, and in 4 the presence of HB virus in hepatocytes was the sole morphologic alteration. The initial liver biopsy was not an accurate predictor of ultimate severity of liver disease because 5 of the 12 patients with virus only or chronic persistent hepatitis subsequently developed chronic active hepatitis or cirrhosis. Clinical liver dysfunction occurred in 8 patients, all of whom had chronic active hepatitis or cirrhosis. Three patients died with hepatic failure and 2 with hepatoma. The risk of death from liver disease in HBsAg-positive renal transplant patients was 5% per patient-year. For comparison, 10 HBsAg-positive patients whose renal failure had been treated by hemodialysis were also studied over a comparable period. Biochemical evidence of persistent liver dysfunction recurred in 1 patient only; 4 patients converted to the HBsAg-negative state; 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 chronic active hepatitis, leading to cirrhosis and death from hepatoma and hepatic failure.

Adolescent↗

Immune reactivity and immunosuppressive intervention in experimental nephritis. II. Effect of TLI on the course of two models of nephritis in the inbred rat.

Fractionated high-dose (3400 rad) total lymphoid irradiation (TLI) induces a unique and prolonged state of immunologic unresponsiveness. The therapeutic efficacy of TLI in immune glomerular disease was explored in two animal models: the accelerated autologous form of nephrotoxic serum nephritis (AA-NTSN) and autologous immune complex nephritis (AICN). LEW rats with established AA-NTSN, subjected to TLI, manifest decreased levels of circulating antibody to the heterologous (sheep) immunoglobulin G (0.4 +/- 0.2 vs 1.2 +/- 0.3 mg/ml, mean +/- SE respectively, p less than 0.01) early post TLI in association with a reduction in histopathology and albuminuria (6.7 +/- 2.2 vs control 19.6 +/- 5.4 mg/24 hr, mean +/- SE, p less than 0.02). Administration of TLI to rats with established AICN effected significant (p less than 0.001) reduction in albuminuria (162 +/- 30 vs 315 +/- 27), serum creatinine (p less than 0.005), and the incidence of lipemia (p less than 0.01) vs controls. Adoptive transfer studies provided no evidence that the sustained beneficial effect of TLI in AICN was suppressor cell mediated. Thus, the observed therapeutic efficacy of TLI in the treatment of experimental nephritis, shown to be related to a reduction in the level of circulating antibody in AA-NTSN, provides a new model system for study of immunity and immunosuppression in primary glomerular disease.

Albuminuria↗

Immune reactivity and immunosuppressive intervention (TLI) in experimental nephritis. I. Immunopathologic correlates in the accelerated autologous form of nephrotoxic serum nephritis.

The progression of histologic changes observed in the accelerated autologous form of nephrotoxic serum nephritis (AA-NTSN) in the inbred LEW rat, ranging from minimal endocapillary proliferation to marked endo- and extra-capillary proliferation together with fibrin deposition and necrosis of glomerular tufts, was closely correlated (day 8) with parallel measures of albuminuria (1.6 leads to 280 mg/24 hr). In the induction phase of AA-NTSN (day 0) a direct linear correlation (r = 0.72, p less than 0.05) was obtained between anti-SGG antibody levels and 24-hr urine albumin excretion. Subsequent observations (day 7) yield an inverse correlation between anti-SGG antibody and albuminuria (r = -0.54, p less than 0.01), and this change was shown to be related to the loss of specific antibody in the urine (r = 0.59, p less than 0.025). Although splenic T cells of rats with AA-NTSN manifest a specific proliferative response to the inducing antigen SGG, and although the magnitude of this proliferative response (day 7) correlates directly with parallel measures of urine albumin excretion (r = 0.71, p less than 0.02), delayed-type hypersensitivity (DTH) to SGG measured by radiometric ear assay was inversely correlated with albuminuria in this model of experimental nephritis (r = 0.80, p less than 0.01). Additional data are presented that strongly suggest that persistent albuminuria at 1 mo after induction of AA-NTSN is independent of ongoing immunopathologic processes. Thus, glomerular injury in AA-NTSN, previously linked to prominent glomerular macrophage accumulation, is shown to be primarily dependent on a brisk antibody response to the planted heterologous (sheep) immunoglobulin, whereas cellular immunity, readily demonstrated in the splenic T cell compartment, is likely to be of lesser import in the pathogenesis of this lesion in the intact animal.

Albuminuria↗

Immune mechanisms in organ allograft rejection. I. Delayed-type hypersensitivity and lymphocytotoxicity in heart graft rejection.

Sublethally irradiated (780 rads) rats receiving fully allogeneic heart transplants were reconstituted with sensitized lymphocytes fractionated into helper and cytotoxic/suppressor T cell subsets according to reactivity with monoclonal antibodies W3/25 and OX8, and the phenotype and functional activity of cells causing rejection was examined. Though the adoptive transfer of T cells of either subset in adequate numbers (0.5 X 10(6] was able to cause rejection, helper T cells were found to be significantly (P less than .02) more potent on a per-cell basis. The reconstituting inocula in this model system acted not simply to amplify a specific immune response by the irradiated host. Cytotoxic T cells appearing in sublethally irradiated heart graft recipients reconstituted with unfractionated T cells were shown to derive from the reconstituting inoculum. Cells with cytotoxic activity for donor-strain thymic blasts were undetectable in spleen or graft of recipients reconstituted with isolated T helper cells (OX8-), but were present in grafts of a high proportion of rats reconstituted with OX8+ cells. T cells within the helper subset (W3/25+ OX8-) were shown to be responsible for adoptive transfer of delayed-type hypersensitivity (DTH) and were phenotypically distinct from cytotoxic cells and their precursors (W3/25- OX8+). Heart graft rejection appears, therefore, to be mediated independently by lymphocyte subsets responsible exclusively for DTH or lymphocytotoxicity. Support for this observation was obtained by demonstrating prominent nonspecific recruitment of lymphocytes and monocytes in graft rejection, as well as frequent direct anatomic contact between infiltrating mononuclear cells and myofibers. This report provides, therefore, substantial evidence for a primary role for DTH in vascularized organ allograft rejection--but at the same time it indicates that cytotoxic T cells may play an independent pathogenic role.

Animals↗

Leukocyte subsets in first-set rat cardiac allograft rejection. A serial immunohistologic study using monoclonal antibodies.

For an immunohistochemical analysis of the cells infiltrating rat cardiac allografts undergoing unmodified first-set rejection, functioning Wistar Furth (RT1u) cardiac allografts transplanted to Lewis (RT1(1)) recipients were arbitrarily removed at days 3-6 posttransplantation, and were evaluated histologically using a series of monoclonal antibodies (MAbs) of known cellular distribution, the binding of which was visualized by an indirect immunoperoxidase technique. Sequestered cells present in cryostat sections were segregated numerically on the basis of staining for MAbs detecting T cells, some NK cells, and neutrophils (W3/13); cytotoxic suppressor T cells and most NK cells (MRC OX8); helper T cells and all macrophages (W3/25); B cells and a macrophage subpopulation (MRC OX6, Ia common part determinant); immature T and B cells (MRC OX7, Thy 1.1); and all leukocytes (MRC OX1, LCA). The proportion of cells stained for each MAb was expressed as a percentage of all estimated leukocytes as determined directly on the hematoxylin counterstained sections. Macrophages expressing the W3/25 and MRC OX6 antigens were enumerated on the basis of intracytoplasmic accumulation of previously administered colloidal carbon. There was a significant fall in the relative proportion of W3/25+ carbon- cells within allografts as a function of time. The proportion of mononuclear cells staining for W3/13 and for MRC OX8 showed no statistically significant variation during the period of study. There was a correlation at all periods between the proportional sum of W3/25+ carbon- cells and MRC OX8+ cells and the proportion of W3/13+ mononuclear cells present. The W3/25+ carbon-:MRC OX8+ ratio showed a significant linear decrease with duration of allograft placement. The proportion of carbon+ cells expressing the MRC OX6 and the W3/25 antigens showed a highly significant rise as a function of time. Nonspecific esterase-stained cells showed a similar sequential pattern. These data provide well defined immunohistologic parameters of leukocyte subsets present in unmodified first-set cardiac allograft rejection in the rat.

Animals↗

Immune mechanisms in organ allograft rejection. II. T helper cells, delayed-type hypersensitivity, and rejection of renal allografts.

The cellular requirements for renal allograft rejection have been assessed by adoptive transfer studies in a rat model. Sublethally irradiated (780 rads) LEW (RT1l) recipients of WF (RT1u) renal allografts were selectively reconstituted with spleen cells from specifically sensitized donors. In some experiments the reconstituting inocula were depleted of SIg+ cells by passage over anti-Ig columns or subjected to additional depletion of cytotoxic T cells (Tc) and their precursors reactive with monoclonal antibody OX8. WF renal allografts underwent acute rejection in the unmodified LEW recipient with day 7 serum creatinines of 6.8 +/- 0.9 mg/dL (mean +/- SD; n = 7), graft histology characterized by marked mononuclear cell infiltration and evidence of a brisk humoral response (complement-dependent cytotoxicity (CDC) titer greater than 2(6] and generation of Tc demonstrable by in vitro monitoring. Sublethally irradiated recipients mounted no detectable immune response, and day 7 serum creatinine and graft histological findings were not significantly different from those obtained in isograft controls. Renal allografts were, however, rejected in sublethally irradiated recipients reconstituted with unfractionated immune spleen cells, as evidenced by functional and histologic criteria (day 7 serum creatinine of 5.5 +/- 1.2 mg/dL; histology characterized by extensive interstitial hemorrhage, fibrinoid necrosis of blood vessels, and polymorphic infiltration). Neither antibody nor Tc appear, in this model, to be required to effect rejection, because recipients reconstituted with inocula depleted of SIg+ cells (day 7 CDC titer less than 2l) or subjected to additional depletion of Tc and their precursors (day 7 lymphocyte-mediated cytotoxicity assay: % specific chromium release at 100/1 E/T ratios less than 5%) underwent acute rejection with a day 7 serum creatinine of 5.0 +/- 1 and 4.3 +/- 1.5 mg/dL, respectively, and histological findings were characterized by marked mononuclear cell infiltration and a paucity of hemorrhage.

Animals↗

A controlled serial ultrastructural tracer study of first-set cardiac allograft rejection in the rat. Evidence that the microvascular endothelium is the primary target of graft destruction.

In order to define the serial morphologic correlates of unmodified first-set cardiac allograft rejection in an inbred rat strain combination, a series of Wistar-Furth cardiac allografts transplanted to normal nonsensitized Lewis recipients were studied as a function of time with the use of well-documented ultrastructural tracer techniques. Colloidial carbon was employed as a vascular label for detection of microvascular endothelial structural alterations, and horseradish peroxidase was used as a tracer probe for localization of cell-membrane permeability dysfunction of allograft endothelium and cardiocytes as well as of elements of the cellular infiltrate. Wistar-Furth to Wistar-Furth syngeneic heart grafts and Wistar-Furth recipients' own hearts provided appropriate control data. This study was demonstrated that severe diffuse loss of functional and structural integrity of the microvascular endothelium precedes the development of extensive damage to cardiac muscle cells and thus provides strong evidence that the allograft microcirculation is the primary target of immunologic injury. In addition, the sequential pattern of injurious changes present in the rejecting allografts was similar to that observed in certain models of delayed-type hypersensitivity and of skin graft rejection, raising the possibility that lymphokine-mediated mechanisms may be of major pathogenetic significance in this setting.

Animals↗

Evidence for complement-induced endothelial injury in vivo: a comparative ultrastructural tracer study in a controlled model of hyperacute rat cardiac allograft rejection.

In order to delineate the potential role of platelet-derived factors and of the direct lytic action of complement in the pathogenesis of endothelial injury in hyperacute allograft rejection, a highly reproducible and rigidly controlled inbred rat cardiac model was studied, utilizing colloidal carbon as a vascular tracer for comparative ultrastructural analysis of the microcirculation. Unmodified allografts were characterized by widespread intramural carbon labeling of the microvasculature, which corresponded to sites of platelet sequestration and extensive endothelial cell disintegration. Under conditions of recipient platelet depletion without concomitant complement depression, carbon-labeled segments of the microcirculation showed widespread endothelial cell disintegration, the ultrastructural features of which were similar to those observed in the unmodified allograft group. The microvasculature of syngeneic heart grafts transplanted to platelet-depleted recipients as well as all platelet-depleted recipients' own hearts showed no similar ultrastructural changes. It is thus concluded that the loss of cellular integrity of the microcirculatory endothelium in hyperacute rat cardiac allograft rejection is not a platelet-dependent phenomenon. The current ultrastructural data combined with previous morphologic studies provide strong evidence that the severe form of endothelial injury observed in this model is mediated by the direct action of activated complement components.

Animals↗

Goodpasture's syndrome treated with plasmapheresis. Report of a case.

A 55-year old man had pulmonary hemorrhage and renal insufficiency. Direct immunofluorescence of a renal biopsy specimen disclosed prominent linear deposition of IgA along glomerular capillary walls. The patient underwent clinical remission following plasma exchange and immunosuppressive therapy.

Anti-Glomerular Basement Membrane Disease↗

Cardiac allograft rejection and enhancement in natural recombinant rat strains.

Cardiac allografts were carried out using rat strain combinations with recombinant haplotypes. Rejection times were determined in unsensitized recipients, recipients that had been immunized to produce hyperacute or accelerated rejection, and recipients that had been i.v. immunized with 10(7) bone marrow cells to produce active enhancement. The graft survival results obtained suggest that there is a major influence of the A region or classical type I transplantation antigens in first set and hyperacute rejection whereas immunization to both A or B region (Ia) antigens may produce markedly prolonged survival. These data suggest major differential influences of major histocompatibility complex (MHC) subregions depending on the specific donor-recipient incompatibility as well as suggesting major influences in these three allograft models depending on the background of the strain used.

Animals↗

The effect of anticomplementary cobra venom factor on hyperacute rat cardiac allograft rejection.

Cobra venom factor was used as a probe to evaluate the effect of depression of recipient hemolytic C3 activity on the sequential morphologic features of hyperacute cardiac allograft rejection in the rat. A series of ACI cardiac allografts transplanted to Lewis recipients presensitized &with ACI skin grafts was studied at arbitrary time periods over the initial 24 hours posttransplantation. The usual morphologic features of hyperacute rejection in this model, platelet aggregation, intravascular fibrin, endothelial destruction, neutrophil infiltration, and myocardial necrosis, were not observed in all allografts when recipient hemolytic C3 activity was virtually undetectable at the time of transplantation. Furthermore, allograft binding of rat C3 was not detected by immunofluorescence, although staining for IgG was commonly encountered. Despite profound depression of recipient hemolytic C3 activity, however, mononuclear cells were observed within the allograft microcirculation by 2 hours posttransplantation, and changes consistent with early cellular rejection were present in allografts examined at 24 hours. This study provides evidence that complement activation by graft-bound alloantibody is a critical effector mechanism of hyperacute rejection in this inbred rat model.

Animals↗

Hyperacute rejection of cardiac allografts in a rat strain with a hereditary platelet function defect.

Graft hypoperfusion secondary to widespread vascular occlusion by recipient-derived platelet aggregates may be a major determinant of hyperacute cardiac allograft rejection in the rat. Since a hereditary platelet aggregation defect, attributed to decreased platelet levels of serotonin and adenine nucleotides and a depressed release reaction, has been described in the fawn-hooded rat strain, the effects of this intrinsic platelet function defect on the time course and morphologic features of hyperacute rejection have been evaluated. A series of nine heterotopic ACI cardiac allografts in fawn-hooded recipients actively immunized with ACI skin grafts were studied. Functional rejection with asystole was observed in all allografts from 8 to 40 minutes posttransplantation. Widespread platelet aggregation, endothelial cell destruction, interstitial widening, and focal myocardial alterations consistent with ischemic damage characterized all allograft. This study indicates that the platelet aggregation defect described for the fawn-hooded rat strain is one that does not alter the time course of the morphologic features of hyperacute cardiac allograft rejection, and thus this platelet aggregation abnormality has no essential role in the pathogenesis of this type of tissue damage.

Animals↗

Nonessential role of neutrophils as mediators of hyperacute cardiac allograft rejection in the rat.

The presence of neutrophils within the graft has been widely emphasized as a characteristic feature of hyperacute rejection, and analogies have been drawn to the Arthus reaction, in which neutrophils are essential mediators of tissue damage. To evaluate the role of neutrophils as mediators of graft destruction in hyperacute rejection, we studied a series of 16 heterotopic ACT strain rat cardiac allografts in skin-presenitized Lewis strain recipients, all of which recieved prior treatment with cyclophosphamide and methotrexate or heterologous rabbit antirat polymorphonuclear globulin. Fourteen recipients showed significant depression in levels of circulating neutrophils prior to transplant, and neutrophils were not detected in 13 allogrates at the time of functional rejection. There was no abrogation of hyperacute rejection in this series and the characteristic pattern of vacular and myocardial damage was not altered by the absence of neutrophils from the graft. Although the possibility that neutrophil-derived agents may contribute to late graft destruction cannot be excluded, this study has shown that neutrophils are neither essential nor specific participants in hyperacute allograft rejection in this model.

Animals↗

A controlled sequential morphologic study of hyperacute cardiac allograft rejection in the rat.

A series of heterotopic cardiac allografts from ACI strain rat donors to ACI skin-presensitized Lewis strain recipients was examined by light and electron microscopy at intervals from 1 minute to 24 hours for a sequential morphologic study of hyperacute rejection. Syngeneic Lewis hearts grafts in ACI skin-presensitized Lewis recipients provided controls. Extensive platelet aggregation throughout the vasculature of the allografts in the presence of a largely intact endothelium was the initial morphologic event, which was present by 1 minute posttransplant and absent in all syngeneic controls. This was followed by widespread endothelial damage. Endothelial damage preceded neutrophil margination and emigration in the graft. Neutrophil degranulation or evidence of phagocytosis was not observed within the 1st hour. At 6 and 24 hours, degranulated forms were common and apparent extrusion of granule contents with progressive ischemic injury. Segmental occlusion of the vasculature by platelet plugs and progressive disruption and loss of capillaries combined with an increase in permeability may result in myocardial ischemia. Neutrophil-derived agents do not appear to be of major significance in hyperacute rejection during the early posttransplant phase, but may play a role in mediating myocardial injury if the allograft survives for alonger period. However, on morphologic grounds, it is suggested that microcirculatory hypoperfusion with resultant ischemia is a major determinant of myocardial damage and graft function. No significant change was noted over the observation period in peripheral neutrophil or platelet counts when compared to syngeneic controls, and a slight reudction in specific cytotoxic antibody titer in the allografts was immediate but very transient.

Animals↗