Histologic and Immunophenotypic Evaluation of Pretreatment Renal Biopsies in Okt3-Treated Allograft Rejections

Visscher, Daniel W.; Carey, John; Oh, Heung K.; Turza, N.; Kupin, Warren; Venkat, K. K.; Zarbo, Richard J.

doi:10.1097/00007890-199105000-00018

Cited by 20 publications

(6 citation statements)

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“…In support of this view are recent reports where the use of specific macrophage inhibitors largely reduced macrophage infiltration and prevented chronic rejection in rat renal allografts.28 In contrast to our findings, Visscher et al 29 have found that intragraft concentrations of individual mononuclear subsets or HLA-DR expression in rejecting allografts do not predict followup graft function and thus poorly reflect the intensity of host immunologic rejection mechanisms. However, their study differs in many respects because they have included patients with acute vascular rejection, their cases were initially steroid resistant and finally OKT3 was used to control rejection.…”

Section: Discussionsupporting

confidence: 71%

Macrophages and HLA‐DR(+) cells in acutely rejecting kidney transplants, predict subsequent graft survival, even after reversal of the acute episode

1998

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Renal graft biopsies from 19 selected patients with acute cellular rejection (ACR) were analysed using a panel of monoclonal antibodies. All patients had only one episode of ACR, which was completely reversible. In 11 patients (group 1) graft function slowly deteriorated over a period of 14 ( &-17) months after the episode. In the remaining eight (group 2 ) graft function remained stable over a similar period of observation. In group 1 there was a significantly increased inflitrate of glomerular and interstitial monocytes/ macrophages (MM) when compared with group 2. Also, the expression of HLA-DR antigen by the tubular cells were stronger in group 1, while T-cells in the glomeruli and the interstitium were equally distributed in both groups. We conclude that large numbers of MM and HLA-DR expressing cells (glomerular, interstitial and tubular) in rejecting kidneys predict a more rapid decline of follow-up renal function despite reversal of the acute episode. This may suggest that subclinical ongoing injury continues in some patients and perhaps more intense immunosuppression is necessary to prevent graft loss.

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Section: Discussionsupporting

confidence: 71%

Macrophages and HLA‐DR(+) cells in acutely rejecting kidney transplants, predict subsequent graft survival, even after reversal of the acute episode

1998

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“…In conclusion, although B7 molecule expression appears to be increased on DC, B cells and macrophages as a consequence of inflammation, aberrant expression of B7 molecules is not detectable on parencbymal cells, wbich do express MHC class II molecules under inflammatory conditions (30)(31)(32)(33)(34)(35). Tbus, it seems likely that antigen presentation by MHC class Il-positive, B7-deficient parenchymal cells may serve to promote tbe induction of tolerance in recently activated or resting memory CD4+ T cells.…”

Section: Cd28andcd152mentioning

confidence: 95%

Antigen presentation by parenchymal cells: a route to peripheral tolerance?

1999

Immunological Reviews

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T-cell activation and the development of efficient immune responses requires the delivery, by the antigen-presenting cell, of two distinct signals. The first results from the engagement of the TCR:CD3:CD4 complex, and the second from the interaction of CD28 with the B7 family of co-stimulatory molecules. In this context, the physiological significance and the functional consequences of antigen presentation by B7-deficient parenchymal cells, which express MHC class II molecules as a result of inflammation, remains a matter of debate. In this paper we have attempted to critically review the often conflicting reports on the functional effects of antigen presentation by epithelial and endothelial cells to T cells, both in vitro and in vivo. Our own findings are summarised in a model which is consistent with the suggestion of an important role for antigen presentation by parenchymal cells in the induction and the maintenance of peripheral tolerance.

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“…Long-term graft survival is not often addressed after OKT3 rescue therapy, and when it is, is usually assessed less than 24 months after treatment, showing rates of graft survival ranging from 50% to 87% [4, 8, 10-12, 14, 18]. These latter studies emphasized that the graft survival was influenced by (a) the nature of the graft (cadaveric vs. living related donor) [18]; (b) the components of the AR, i.e., the presence or absence of either vascular lesions or chronic lesions [12,13]; (c) the CsA trough levels at the beginning of OKT3 therapy [6]; (d) time between initiation of OKT3 therapy and the initial diagnosis of AR [6,8]. Another factor that might influence short-term graft survival following OKT3 as rescue therapy is the concomitant administration of CsA: CsA is usually withheld during OKT3 therapy and resumed 2 to 3 days before its end to reduce the risk of CsA nephrotoxicity and over-immunosuppression [3,5,6,10,11,18].…”

Section: Discussionmentioning

confidence: 99%

“…The efficacy of Orthoclone OKT3, an IgG2 murine monoclonal antibody which reacts with the Â chain of the T cell antigen receptor in the reversal of rejection episodes that have failed to respond either to methylprednisolone pulses or to polyclonal antilymphocyte therapies, has been well documented in a large number of trials [1][2][3][4][5][6][7][8]. Hence the overall rejection reversal rate ranges between 74% and 100% [5,[8][9][10][11][12][13], but may be lower when acute cellular rejection is associated either with vascular rejection or with chronic lesions [12,13]. This reversal rate does not seem to be dependent upon immediate post-transplant immunosuppression i.e., CsA, azathioprine (AZA) and steroids (CS) versus quadruple sequential therapy (AZA, CS, polyclonal antilymphocyte globulins followed by CsA) [14].…”

Section: Introductionmentioning

confidence: 99%

Predicting Factors of Long-Term Results of OKT3 Therapy for Steroid Resistant Acute Rejection following Cadaveric Renal Transplantation

et al. 1999

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In this retrospective study, we evaluated the histological and biological predictors of long-term response of renal transplant (RT) patients treated with orthoclone OKT3 for steroid resistant acute rejection (AR). Seventy-three patients, aged 37 ± 12 years, were included in this study between March 1987 and December 1996. All the patients but one had received sequential quadruple immunosuppression (polyclonal antilymphocyte globulins; steroids; azathioprine, and cyclosporin A). OKT3 (5 mg/day for 10 days) was administered for biopsy-proven steroid resistant AR i.e., after 3 consecutive pulses of methylprednisolone (10 mg/kg each). This was the first AR in 46 cases, the second AR in 22 cases and the third AR in 4 cases. Renal histology (Banff) showed borderline (BL) changes in 18 patients, grade I AR in 28 patients; grade II AR in 22 patients, and grade III AR in 5 patients. When treatment with OKT3 commenced (107 ± 18 days post-transplantation) the mean serum creatinine (SCr) level was 325 ± 195 μmol/l; this had decreased to 191 ± 106 μmol/l by the end of OKT3 therapy. The immediate response to OKT3 therapy i.e., within the first month, was not dependent on the histological score. Twenty-six patients (35%) subsequently experienced at least one more AR episode of whom 4 were retreated with OKT3. The overall patient’s survival was 94.5% at last follow-up. The overall cumulative graft survival was 64.5% at 2 years, 52.5% at 5 years, and 40.5% at 8 years. The graft survival (5 years) tended to depend on the initial histological score, i.e. BL 30%; grade I 66%; grades II and III 55.5% (p = 0.08). In a multiple logistic regression analysis we tried to identify independent factors that would predict that a graft would still be functioning at least 2 years after OKT3 therapy. We therefore analyzed the following parameters: donor and recipient’s age; gender; cold ischemia time; HLA matching; panel reactive antibodies (PRA) prior to grafting; previous transplantation(s); total number of AR episodes; the time of onset of the AR treated by OKT3 compared to the other AR; the time of onset of the AR treated by OKT3; SCr levels at days 0, 10 and 30 after OKT3 therapy; histological score (Banff) i.e., the magnitude of AR and the presence or absence of chronic lesions. The only independent factors which would predict that a graft was still functioning 2 years after OKT3 therapy were: PRA <25% (Odds ratio (OR) 7.68 (1.15–51.3); p = 0.035); a grade I AR (OR 10.52 (1.18–93.5); p = 0.035); SCr level 1 month after OKT3 therapy (OR 0.935 (0.87–1.002); p = 0.05). HLA matching and the presence of histological chronic lesions were nearly significant (p = 0.06 and 0.09 respectively). In conclusion, this retrospective study shows that independent predictors of the long-term response to OKT3 therapy for AR in RT patients are the magnitude of pre-transplant PRA, the histological score, and the SCr level one month after OKT3 therapy.

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Histologic and Immunophenotypic Evaluation of Pretreatment Renal Biopsies in Okt3-Treated Allograft Rejections

Cited by 20 publications

References 0 publications

Macrophages and HLA‐DR(+) cells in acutely rejecting kidney transplants, predict subsequent graft survival, even after reversal of the acute episode

Macrophages and HLA‐DR(+) cells in acutely rejecting kidney transplants, predict subsequent graft survival, even after reversal of the acute episode

Antigen presentation by parenchymal cells: a route to peripheral tolerance?

Predicting Factors of Long-Term Results of OKT3 Therapy for Steroid Resistant Acute Rejection following Cadaveric Renal Transplantation

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