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Biomedical subjects

H Auchincloss

Publications and source records attributed to H Auchincloss.

At least 73 records · Page 4Linked to original sources
PubMed1992

Symptomatic cytomegalovirus disease in the cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3.

A prospective study to investigate risk factors for CMV disease was conducted in 94 renal transplant recipients. CMV disease was defined as either unexplained fever for greater than 3 days with viremia or unexplained fever for greater than 3 days with isolation of CMV from the urine or throat wash and at least one of the following: leukopenia, elevated serum alanine aminotransferase, or biopsy-proved invasive tissue infection of the lung or gastrointestinal tract. Fifty-three patients received immunosuppressive regimens consisting of prednisone and cyclosporine, with or without azathioprine. The remaining 41 patients were treated with these agents plus OKT3 (21 received OKT3 to treat rejection, 20 received OKT3 prophylactically). Thirty-seven patients were at minimal risk of CMV disease (donor and recipient seronegative for CMV); 12 patients were at risk of primary disease (donor seropositive, recipient seronegative), and 45 were at risk of reactivation disease (recipient seropositive at the time of transplantation). The incidences of CMV disease in the 3 groups were 0%, 58%, and 36%, respectively. Although the incidence of CMV disease in patients at risk of primary disease was not influenced by the immunosuppressive regimen, immunosuppression had a profound effect on the occurrence of CMV disease in CMV-seropositive transplant recipients. The incidence of CMV disease in those receiving OKT3 was 59%; but only 21% in those who did not receive OKT3. OKT3 increased the risk of CMV disease five-fold (odds ratio 5.2 (95% confidence limits 1.4-17.5)). In the CMV-seropositive patient, OKT3 was also the most important predictor of CMV disease by multivariate analysis (P less than 0.002). A pilot study of preemptive therapy with ganciclovir (2.5 mg/kg daily during OKT3 therapy) in 17 patients decreased the incidence of CMV disease without appreciable toxicity.

Adult↗
PubMed1992

Evidence that multiple defects in cell-surface molecule interactions across species differences are responsible for diminished xenogeneic T cell responses.

The purpose of the present study was to identify which of the several possible defects in cell-surface-molecule interactions are responsible for diminished mouse helper T cell responses to xenoantigens. We measured primary mouse anti-monkey, anti-pig, and anti-human proliferation in vitro in experimental systems in which potential defects were partially corrected by lymphokine supplementation and/or the use of transgenic or hybridoma cell populations. We found that the diminished mouse helper T cell responses to xenoantigens result from at least two defects in cell-surface-molecule interactions between T cells and xenogeneic APCs, specifically TCR and/or CD8 interactions with xenogeneic class I MHC molecules and accessory molecule interactions with their ligands (probably LFA-1 with ICAM-1/ICAM-2 and/or LFA-2 with LFA-3). Other investigators have identified additional defects, such as in lymphokine function across species differences. Thus, there appear to be multiple defects responsible for the diminished cellular immune response to xenoantigens.

Animals↗
PubMed1992

Liver transplantation for primary hepatic cancer.

Although early survival following transplantation for primary hepatic cancer is excellent, previously reported high recurrence rates have generally discouraged liver replacement for this indication. Since the inception of the Boston Center for Liver Transplantation (BCLT) in 1983, 33 of 383 (8.6%) liver allograft recipients have undergone orthotopic transplantation as definitive treatment for otherwise unresectable cancer. Diagnoses included hepatocellular carcinoma (HCCA) in 24 patients (73%), and cholangiocarcinoma (CHCA) in 9 patients (27%). Actuarial survival rates for patients with hepatocellular carcinoma were 71%, 56%, and 42% at 1, 2, and 3 years, respectively. The actuarial survival rates for patients with cholangiocarcinoma were 89% at 6 months, and 56% at 1, 2, and 3 years. Of the nine patients with cholangiocarcinoma, 56% (5/9) developed recurrent disease. Although this recurrence rate is disheartening, because of the lack of other morbidity, long-term survival in these patients is comparable to patients with HCCA. In contrast, recurrent hepatocellular carcinoma developed in 25% of recipients (5/20) who survived longer than 3 months posttransplantation. Other causes of death in patients with hepatocellular carcinoma included perioperative complications, 16.6% (4/24); sepsis, 8.3% (2/24); coronary artery disease, 4.2% (1/24); and lymphoma, 4.2% (1/24). Favorable prognostic factors included: primary tumor less than 3 cm in size and absence of associated cirrhosis. These results emphasize that orthotopic liver transplantation can provide a long-term cure for approximately 50% of patients whose primary hepatic malignancy is unresectable by conventional procedures.

Adenoma, Bile Duct↗
PubMed1991

Hard graft? Future challenges in transplantation.

A small group of transplantation surgeons, immunologists and molecular biologists gathered in Vienna in early February to discuss the prospects for organ transplantation. Participants at the meeting were challenged with setting goals for transplantation research and with speculating on how this research might influence the practice of transplantation in the next two decades. Some goals were set, but the most vigorous discussion focused on the existing barriers that stand in the way of achieving these goals.

Antigens↗
PubMed1991

Long-term metabolic and quality of life results with pancreatic/renal transplantation in insulin-dependent diabetes mellitus.

Evaluation of whole-organ pancreas transplantation in the therapy of IDDM has been difficult because of generally poor graft survival and significant complications in past experience. We report a technically successful simultaneous pancreas/kidney transplant program with patient and graft survival of 85% over 3 years of follow-up (mean 21 months) in 33 subjects with IDDM. Glucose metabolism was normalized without need for exogenous insulin immediately posttransplant in all but one recipient and remained normal in 85% of recipients. The outcome in pancreas/kidney recipients was compared with that in 18 insulin-dependent diabetic recipients of kidney transplant only performed in the same period. Quality of life was assessed with one general and one diabetes-specific questionnaire. General quality of life issues improved significantly in both pancreas/kidney and kidney recipients, but diabetes specific quality of life improved only in the pancreas/kidney recipients. Pancreas/kidney recipients required twice as long a period of hospitalization for the transplant and two times as many readmissions for a variety of complications. Only a minority of hospital admissions was strictly attributable to the pancreas graft. Of the five deaths in the pancreas/kidney recipients, two were attributable to the pancreas transplant. Pancreas transplantation in IDDM can now be accomplished with a high degree of success, resulting in normalized glucose metabolism and with overall mortality similar to kidney transplantation alone. Successful pancreas transplantation improves quality of life with respect to diabetes but this benefit is accomplished at a cost of increased hospital admissions and complications related to the transplanted pancreas. The effects of pancreas transplantation on the long-term complications of insulin-dependent diabetes remain unknown.

Adult↗
PubMed1991

Spontaneously hypertensive and Wistar Kyoto rats are genetically disparate.

Spontaneously hypertensive rats (SHR) are one of the most common animal models used to study essential hypertension in humans. Because SHR and normotensive Wistar Kyoto (WKY) rats were both established from the same parental, normotensive Wistar stock, WKY animals have been used almost exclusively as control animals in studies of SHR. Recently, the suitability of WKY rats as normotensive controls for SHR has been challenged. To establish whether or not SHR and WKY rats share the same immunologic backgrounds, we initially performed a series of skin grafting experiments on these animals. In all cases, grafts of SHR donor skin to WKY recipients and of WKY donor skin to SHR recipients resulted in complete rejection within 7 to 10 days. In addition, grafts of WKY donor skin to other WKY recipients resulted in graft rejection. By contrast, skin grafts between SHRs were always accepted. To further characterize the genetic distinctions between SHR and WKY rats, allelic profiles based on a series of immunologic and biochemical markers were established for each strain. These findings clearly establish that SHR and WKY rats differ at the major histocompatibility complex, in specific blood group antigens, and in a panel of isozymic markers. Moreover, whereas SHRs have the same genetic profiles irrespective of source, some colonies of WKY rats are outbred, as judged by their variant allelic profiles.

Animals↗
PubMed1990

Xenogeneic proliferation and lymphokine production are dependent on CD4+ helper T cells and self antigen-presenting cells in the mouse.

We studied proliferation and interleukin 2 production by B6 mouse spleen cells in response to stimulation by irradiated cynomolgus monkey spleen cells and compared the results with responses against whole MHC-disparate allogeneic controls (BALB/c). We found that (a) primary xenogeneic helper responses were absent, whereas primary allogeneic responses were brisk, (b) secondary xenogeneic helper responses were dependent on CD4+ T cells and responder antigen-presenting cells (APCs), whereas allogeneic responses could be mediated by either CD4+ or CD8+ T cells independently and were primarily dependent on the presence of stimulator APCs, and (c) secondary xenogeneic helper responses were blocked by an antibody directed against responder class II MHC molecules. These results suggest that mouse helper T cells recognize disparate xenoantigens as processed peptides in association with self class II MHC molecules, similar to the recognition of nominal antigens and unlike direct allo-recognition.

Animals↗
PubMed1990

Long-term, low-dose cyclosporine treatment of renal allograft recipients. A randomized trial.

Ninety-two adult renal allograft recipients, receiving baseline immunosuppression with CsA and prednisone, were assigned randomly to one of the following regimens. CsA was discontinued (D/C group) in 47 recipients who were then maintained on Aza and prednisone; or Aza was added to continued low-dose CsA and prednisone (triple drug [TD] group) in 45 patients. Entry into the study required an absence of rejection and a stable creatinine for at least four months prior to randomization. The mean month of randomization was 8.34 +/- 2.9 for the D/C group, and 7.2 +/- 3.2 for the TD group. Following randomization, a significantly greater rate of rejection (P less than .01) was observed in the D/C group (40%) than in the TD group (13%). With a mean follow-up of 30 months, 41/47 of D/C allografts (87.2%) and 39/45 TD allografts (86.6%) were functioning. Nevertheless, rejection had a persistent adverse effect on allograft function, in both the D/C and TD groups, up to 36 months following randomization. Parameters such as donor-type and rejection prior to randomization did not identify recipients at risk for rejection following randomization. Therefore, although the CsA withdrawal regimen might be ideal, the opportunity to select appropriate candidates remained elusive. In contrast, the safety of the TD regimen became apparent. Neither significant nephrotoxicity nor hypertension was observed, and the opportunity for less daily prednisone was evident. Despite its additional cost, the TD regimen utilizing indefinite low-dose CsA, is preferred.

Adult↗
PubMed1990

Xenograft rejection of class I-expressing transgenic skin is CD4-dependent and CD8-independent.

B10.PD1 mice are transgenic animals expressing a class I MHC antigen of pigs. B10.PD1 skin graft survival on B6 mice was prolonged by anti-CD4 antibody treatment in vivo but not by anti-CD8 treatment. These results suggest: (1) that the defect in cell-mediated recognition of xenografts involves an interaction with the xeno-MHC antigens themselves and not with the cells which express them; (2) that antigen processing and presentation of xeno-antigens on responder-type APCs is required in vivo; and (3) that CD8-independent, possibly noncytotoxic, mechanisms of xenograft rejection may exist.

Animals↗
PubMed1989

Murine CD8+ T cell helper function is particularly sensitive to cyclosporine suppression in vivo.

In order to investigate the mechanism of action of cyclosporine (CsA) in vivo the drug was used to prolong the survival of different types of allogeneic skin grafts on mice under different conditions. Lower doses of CsA were necessary to prolong class I-disparate grafts than to prolong class II-disparate grafts than to prolong whole MHC-disparate grafts. Second set skin grafts, even of class I-only disparity, could not be prolonged even by higher doses of CsA. Primary class I-disparate grafts, which survived at a low dose of CsA, were rejected at the same dose if a second inducer graft was also placed expressing the same class I Ag plus other mismatched class II Ag. A suboptimal dose of CsA was synergistic with an anti-CD4 mAb but not with an anti-CD8 antibody for whole MHC-mismatched grafts. These results support the notion that CsA interferes with helper T cell function in vivo and suggest that CD8+ helper function is particularly sensitive to CsA suppression.

Animals↗
PubMed1989

Xenogeneic skin graft rejection is especially dependent on CD4+ T cells.

B6 mice were treated in vivo with anti-CD4, anti-CD8, or both anti-T cell antibodies together in an effort to prolong xenogeneic compared with allogeneic skin graft survival. Mice treated with anti-CD4 antibody showed prolonged survival of xenogeneic monkey or rabbit skin even after they had rejected whole MHC-disparate allogeneic mouse skin. Furthermore, the addition of cyclosporine was synergistic with the anti-CD4 antibody in prolonging graft survival. These results suggest that the cell-mediated response to xenogeneic antigens is especially dependent on CD4+ lymphocytes, a feature shared by the response to allogeneic minor histocompatibility antigens. In addition, the results suggest a possible approach to clinical immunosuppression for some forms of xenogeneic transplantation.

Animals↗
PubMed1989

In vivo use of monoclonal antibodies against murine T cell antigens.

Experiments were performed seeking conditions for the optimum use of anti-T cell monoclonal antibodies in vivo in mice. Anti-L3T4 (CD4) and anti-Lyt2 (CD8) antibodies of different subclasses (IgG2b, IgG2a, and IgM) and species (rat or mouse) were used. The results showed that (i) intraperitoneal compared to intravenous administration of the different antibodies achieved the same serum levels whether in the presence or absence of the recipient's thymus; (ii) repeated treatment with a rat IgM anti-L3T4 or a rat IgG2b anti-Lyt2 antibody was followed by inability to detect serum levels of each antibody; (iii) in vivo treatment with these antibodies caused target cell lysis, target antigen masking without cell destruction, or target antigen modulation without cell destruction and the particular effect of a given antibody could not be predicted by its isotype or specificity; (iv) neither the C5 component of complement nor antibody-dependent cell-mediated cytotoxicity mediated the action of GK1.5 antibody in vivo; (v) dose-response curves of in vivo potency of a given antibody could not be predicted by in vitro assays; (vi) thymocytes were depleted by monoclonal antibody treatment by using 1000-fold more antibody than needed to deplete peripheral lymphocytes; (vii) the rate of return of target T cells after depletion in nonthymectomized mice depended on the dose of the antibody; and (viii) thymectomy prolonged the effect of most, but not all antibodies. In thymectomized mice, CD8+ cells remained almost undetectable for prolonged periods of time after depletion while CD4+ cells returned to approximately 30% of their original level and remained constant over time after initial complete depletion. These results provide useful data for the effective use of monoclonal anti-T cell antibodies in mice. They stress the difficulty of predicting the in vivo effects of monoclonal antibodies without actually testing them in vivo. They include new insights into mechanisms of action of monoclonal antibodies and the role of thymectomy in prolonging their effect. They describe the unrecognized ability of antibodies to deplete thymocytes.

Animals↗