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Biomedical subjects

H Auchincloss

Publications and source records attributed to H Auchincloss.

At least 55 records · Page 3Linked to original sources
PubMed1995

Xenotransplantation.

The need for an alternative source of donor organs, together with the expansion of scientific data in this field, has focused attention on xenotransplantion as a possible alternative to allotransplantation in the treatment of patients with end-stage disease of vital organs. However, xenotransplantation is rarely successful. Not only are the immunological barriers to the acceptance of xenogeneic tissue more powerful than those seen in allotransplantation, but the potential for the transmission of xenograft-associated zoonoses to the human host at the time of transplantation is also present. In addition, data on the physiological performance of the xenograft in the human environment are lacking, although a few functioning xenografts have been shown to be capable of supporting human life. Although progress has been made in clarifying some of the barriers to xenotransplantation and in defining appropriate therapeutic interventions, including interventions aimed at the removal of natural antibody and at the limitation of complement activation, xenotransplantation is not yet a viable alternative to allotransplantation in the clinical setting.

Animals↗
PubMed1994

Indirect recognition by helper cells can induce donor-specific cytotoxic T lymphocytes in vivo.

In vitro studies have revealed that help for cytotoxic T lymphocyte (CTL) induction can be mediated through several pathways, including direct recognition of allogenic class II antigens by CD4+ cells, direct recognition of allogeneic class I antigens by "CD4-independent" CD8+ cells, and "indirect" recognition of peptides of alloantigens presented in association with self class II molecules. Whereas good evidence for the two direct pathways is available in vivo, there is relatively little evidence to show that indirect recognition can initiate graft rejection. This study examined the role of indirect allorecognition during the generation of CTLs in mice as they rejected major histocompatibility complex (MHC) class II-deficient skin after depletion of CD8+ T cells in vivo. Recipients were depleted of CD8+ T cells by in vivo treatment with anti-CD8 monoclonal antibody and then grafted with allogeneic skin lacking MHC class II antigens. The mice rejected the skin grafts rapidly. Although flow cytometry showed marked depletion of CD8+ T cells in these mice, we found that (a) CD8+ CTLs were generated and sensitized to MHC class I antigens of the donor; (b) the generation of the CD8+ CTLs required the help in vivo of CD4+ cells, as well as priming with the allogeneic skin graft; and (c) the CD4+ T helper cells were sensitized indirectly to donor peptides presented in association with class II antigens on recipient antigen-presenting cells. These results provide evidence that indirect recognition can provide effective help for CTL induction during graft rejection, even when the cytotoxic T cells are sensitized by determinants expressed only on the donor graft.

Animals↗
PubMed1994

Second renal transplantations. Ethical issues clarified by outcome; outcome enhanced by a reliable crossmatch.

OBJECTIVE: To determine whether the appropriate use of scarce donor resources has been accomplished by renal retransplantation by reviewing the initial and long-term outcomes of second-renal transplant recipients at the Massachusetts General Hospital, Boston. PATIENTS AND RESULTS: With a mean follow-up of nearly 5 years following transplantation, 54 (68%) of 80 second-transplant recipients had functioning allografts (allograft failure was defined by patient death or a return to dialysis). Rejection was the most common cause of failure (14 [54%] of 26 patients). The 1-, 3-, and 5-year actuarial allograft survival rates were 86%, 78%, and 69%, respectively, which were not significantly different from the survival rates of primary allografts at this center. These results support the continued approach of providing both cadaver-donor and living-donor renal allografts for recipients whose primary renal allograft has failed. The antiglobulin crossmatch may have contributed to the successful outcome by accurately determining compatibility and by averting early rejection failures. CONCLUSIONS: Health care policy reviewers should clearly distinguish the prospects for successful second renal transplants from the outcomes of extrarenal retransplantation. Moreover, because excellent second-renal allograft survival is attainable and comparable to primary-renal allograft survival and because the costs are comparable, restricting suitable patients to subsequent lifelong dialysis becomes unethical.

Adult↗
PubMed1994

Mechanisms of transplantation tolerance.

Transplantation tolerance, the long-term acceptance of grafted tissue in the absence of continuous immunosuppression, remains an elusive goal in humans, but it has been achieved in animal models using numerous approaches. The mechanisms behind graft acceptance vary according to the means used to create the state of acceptance. Several major mechanisms can now be recognized. While thymic deletion of T cells appears to be a mainstay of self-tolerance, its role in transplantation tolerance now seems to be less significant. In contrast, extrathymic mechanisms of transplantation tolerance seem to be major factors in long-term graft acceptance. If donor antigens are presented in a nonimmunogenic manner on the graft, e.g. due to modification of graft tissue by culture, peripheral T cells of the recipient may ignore the graft. Alternatively, nonstimulatory presentation of donor antigens on graft tissue can induce a state of unresponsiveness in recipient T cells, i.e. anergy, rather than activating them to destroy the graft. Suppression mechanisms also operate to control graft rejection and may be specific or nonspecific in nature. Specific suppression mechanisms might act in an idiotype or antigen-specific fashion, and evidence is accumulating that this may be mediated through the elaboration of cytokines. Donor antigen-specific T cells may be activated to produce "protective" cytokines which then regulate the generation of destructive T cells. Future therapies will be aimed at affecting graft acceptance through these peripheral mechanisms.

Animals↗
PubMed1994

Cell-mediated xenoresponses: strong or weak?

Cell-mediated responses to xenoantigens are different from those to alloantigens. CD4+ T cells are especially important in xenoresponses and depletion of CD4+ T cells can prolong survival of xenografts better than allografts in some circumstances. The difference between the two responses is due in part to the relative weakness of direct T-cell responses stimulated by xenogeneic antigen-presenting cells. Instead, T cells tend to require that donor antigens be processed and presented indirectly in association with the MHC antigens on their own APCs. The defect in direct stimulation is due to failure of some of the several T cell/APC interactions when the receptors and ligands of these interactions come from different species. Although the cell-mediated response to xenografts is different, it remains very strong. The mechanism by which CD4+ cells cause xenograft destruction remains to be determined, but a better understanding of this mechanism may help to select the most useful types of immunosuppression for xenogeneic transplantation.

Animals↗
PubMed1994

Management of the renal allograft recipient: immunosuppressive protocols for long-term success.

To determine the benefits of long-term cyclosporine (CsA) immunosuppression, renal allograft recipients were randomly assigned to a protocol of either: CsA+azathioprine (Aza)+prednisone (TD), or to a protocol in which CsA was discontinued from the regimen of Aza+prednisone (CsA D/C). With a mean follow-up of nearly 7 years since transplantation, 30/47 (64%) CsA D/C and 27/45 (60%) TD had functioning allografts. Although long-term survivals were similar, hazards of the CsA D/C protocol were evident (40% rate of acute rejection following CsA D/C). Conversely, continued CsA in the TD protocol provided the opportunity for prednisone reduction, or even complete prednisone withdrawal in selected patients. A TD protocol which can provide equivalent long-term success, and eventually lower or omit prednisone, is preferable to a protocol of CsA D/C.

Acute Disease↗
PubMed1993

Mice lacking major histocompatibility complex class I and class II molecules.

Mice lacking major histocompatibility complex (MHC) antigens were generated by mating beta 2-microglobulin-deficient, and therefore class I-deficient, animals with MHC class II-deficient animals. When housed under sterile conditions, the resulting MHC-deficient mice appear healthy, survive for many months, and breed successfully. Phenotypically, MHC-deficient mice are depleted of CD4+ and CD8+ T cells in peripheral lymphoid organs due to a lack of appropriate restricting elements. In contrast, the B-cell compartment of these animals appears intact, and MHC-deficient mice can mount specific antibody responses when challenged with a T-independent antigen. Spleen cells from MHC-deficient animals are poor stimulators and responders in a mixed lymphocyte reaction. Despite their relatively weak cellular immune responses in vitro, MHC-deficient mice reject allogeneic skin grafts with little delay, and grafts from MHC-deficient animals are rapidly rejected by normal allogeneic recipients. Taken together, these results emphasize the plasticity of the immune system and suggest that MHC-deficient mice may be useful for examining compensatory mechanisms in severely immunocompromised animals.

Animals↗
PubMed1993

The role of "indirect" recognition in initiating rejection of skin grafts from major histocompatibility complex class II-deficient mice.

In vitro studies have revealed several pathways by which T cells can respond to alloantigens, including CD4+ direct responses to allogeneic class II antigens, CD8+ direct responses to allogeneic class I antigens, and CD4+ "indirect" responses to peptides of alloantigens presented in association with responder class II molecules. In vivo studies of skin graft rejection, however, have so far provided clear evidence for the contribution of only the two direct pathways and not for indirect recognition. We have used major histocompatibility complex class II-deficient mice as donors to test the role of indirect recognition in rejection of skin grafts. Class II-deficient skin was always rejected without delay by normal recipients. Removal of recipient CD8+ cells (to leave the animals dependent on CD4+ function) or depletion of recipient CD4+ cells revealed that CD4+ cells were usually involved and sometimes absolutely required in this rapid rejection. Since the donor grafts lacked class II antigens, the CD4+ cells must have recognized donor antigens presented in association with recipient class II molecules. These results therefore indicate that indirect recognition can initiate rapid skin graft rejection.

Animals↗
PubMed1993

Class II-positive hematopoietic cells cannot mediate positive selection of CD4+ T lymphocytes in class II-deficient mice.

Generation of immunocompetent alpha/beta T-cell receptor-positive T cells from CD4+CD8+ thymocytes depends upon their interaction with thymic major histocompatibility complex (MHC) molecules. This process of positive selection provides mature T cells that can recognize antigens in the context of self-MHC proteins. Previous studies investigating haplotype restriction in thymic and bone-marrow chimeras concluded that radioresistant thymic cortical epithelium directs the positive selection of thymocytes. There is controversy, however, as to whether intra- or extrathymic radiosensitive bone marrow-derived macrophage and dendritic cells also can mediate positive selection. To determine whether CD4+ T cells can be positively selected by hematopoietic cells, we generated chimeric animals expressing MHC class II molecules on either bone marrow-derived or thymic stromal cells by using a recently produced strain of MHC class II-deficient mice. CD4+ T cells developed only when class II MHC molecules were expressed on radioresistant thymic cells. In contrast to what recently has been observed for the selection of CD8+ T lymphocytes, MHC class II-positive bone marrow-derived cells were unable to mediate the selection of CD4+ T cells when the thymic epithelium lacked MHC class II expression. These data suggest that CD4+ and CD8+ T cells may be generated by overlapping, but not identical, mechanisms.

Animals↗
PubMed1993

A phase I trial of immunosuppression with anti-ICAM-1 (CD54) mAb in renal allograft recipients.

Several adhesion molecules contribute to the interaction between T cells and antigen presenting cells or target cells. Leukocyte function-associated molecule-1 (LFA-1[CD11a/CD18]) and intercellular adhesion molecule-1 (ICAM-1 [CD54]) are one such critical adhesive receptor-counter-receptor combination. The importance of ICAM-1 dependent adhesion in the rejection response was initially demonstrated in cynomolgus renal allograft recipients treated with the anti-ICAM-1 murine monoclonal antibody BIRR1. BIRR1 also appeared to limit ischemic damage in these animals. A Phase I clinical trial has subsequently been completed in 18 patients who received cadaver donor renal allografts at high risk for delayed graft function (prolonged preservation time, highly-sensitized recipient). An adequate BIRR1 serum level was associated with significantly less delayed graft function (P < .01) and rejection (P < .01). In 1-hr biopsies, mouse IgG was detected along the endothelium of the vessels and glomeruli in the graft. There were no instances of primary non-function (PNF), and current allograft survival (followup: 16-30 months) in these "high-risk" mAb-treated patients is 78%. There were 3 instances of PNF and a graft survival rate of 56% in the recipients of the contralateral kidney allografts treated with conventional immunosuppression. No significant "first-dose" effect was associated with BIRR1 administration. These results establish a dosing schedule and the clinical safety of BIRR1. They also suggest that inhibition of leukocyte adhesion by mAb therapy may be useful in controlling allograft rejection and possibly in limiting reperfusion injury. Thus, these observations support the clinical importance of accessory molecules in T cell function. We hypothesize that anti-CD54 mAb acts by blocking leukocyte adhesion to the endothelium, thereby interfering with sensitization or target cell interaction.

Adolescent↗
PubMed1992

Trimethoprim-sulfamethoxazole compared with ciprofloxacin for the prevention of urinary tract infection in renal transplant recipients. A double-blind, randomized controlled trial.

BACKGROUND: Prophylaxis with low-dose trimethoprim-sulfamethoxazole has been shown to be cost-effective in the prevention of urinary tract infections, pyelonephritis, urosepsis, and pneumocystis pneumonia in renal transplant recipients. Ciprofloxacin, effective against almost all urinary tract pathogens in this patient population, represents a promising alternative prophylactic agent for patients unable to tolerate trimethoprim-sulfamethoxazole due to toxicity. METHODS: We conducted a randomized, double-blind trial to compare low-dose trimethoprim-sulfamethoxazole with ciprofloxacin for the prevention of urinary tract infections in renal transplant recipients. Patients received either ciprofloxacin (250 mg) or trimethoprim-sulfamethoxazole (80 mg trimethoprim, 400 mg sulfamethoxazole) daily for 6 months following transplantation. Treatment was considered successful if patients completed the 6-month course and 3-month follow-up period without evidence of urinary tract infection or drug-related toxicities. RESULTS: Of 103 eligible patients, 51 received ciprofloxacin and 52 received trimethoprim-sulfamethoxazole. At 6 months, treatment was successful in 75% (38 of 51) receiving ciprofloxacin and 71% (37 of 52) treated with trimethoprim-sulfamethoxazole (P = 0.87, relative risk 1.04, 95% confidence limits 0.83 to 1.33). Thirteen patients (25%) receiving trimethoprim-sulfamethoxazole withdrew from the study-4 for resistant urinary tract infection and 9 for drug-related toxicity, while 3 (6%) of the patients receiving ciprofloxacin withdrew because of drug-related toxicity (P = 0.016, relative risk of urinary tract infection or adverse event 0.24, 95% confidence limits 0.07 to 0.78). At 9 months, all 38 patients who completed the 6-month course of ciprofloxacin remained free of urinary tract infection, while an additional 4 patients who had received trimethoprim-sulfamethoxazole prophylaxis (total of 8 patients over the 9 months) developed urinary tract infections (P = 0.006, Fisher's exact test for urinary tract infection alone). Pneumocystis pneumonia occurred in a total of 7 (14%) patients who were randomized to ciprofloxacin, but 2 of the 7 had withdrawn from the study at least 2 weeks prior to the diagnosis of pneumocystis pneumonia. There were no cases of pneumocystis pneumonia in patients receiving trimethoprim-sulfamethoxazole (P = 0.006). Following completion of the study, monthly aerosolized pentamidine administered in conjunction with ciprofloxacin has provided complete protection against urinary tract infection and pneumocystis pneumonia in 30 transplant recipients unable to tolerate trimethoprim-sulfamethoxazole therapy. CONCLUSIONS: Ciprofloxacin is at least as effective as trimethoprim-sulfamethoxazole in the prevention of urinary tract infection in renal transplant recipients, and is better tolerated. Ciprofloxacin prophylaxis is associated with a higher incidence of pneumocystis pneumonia than is trimethoprim-sulfamethoxazole therapy. An uncontrolled follow-up study suggests that ciprofloxacin prophylaxis combined with monthly aerosolized pentamidine may be efficacious in preventing both urinary tract infection and pneumocystis pneumonia in renal transplant recipients.

Adult↗
PubMed1992

Skin graft rejection by beta 2-microglobulin-deficient mice.

Mice homozygous for a beta 2-microglobulin (beta 2-m) gene disruption lack beta 2-m protein and are deficient for functional major histocompatibility complex class I (MHC-I) molecules. The mutant mice have normal numbers of CD4+8- T helper cells, but lack MHC-I-directed CD4-8+ cytotoxic T lymphocytes (CTLs). In this study we used the beta 2-m mutant mice to study the importance of MHC-I-directed immunity in skin graft rejection. Our results indicate that MHC-I-directed CD8+ CTLs are not essential in the rejection of allografts with whole MHC or multiple minor H differences. However, the absence of MHC-I-guided immunity profoundly reduces the ability of mutant mice to reject H-Y disparate grafts. In addition, we show that natural killer cells which vigorously reject MHC-I-deficient bone marrow grafts, are not effective in the destruction of MHC-I-deficient skin grafts.

Animals↗
PubMed1992

Comparison of GK1.5 and chimeric rat/mouse GK1.5 anti-CD4 antibodies for prolongation of skin allograft survival and suppression of alloantibody production in mice.

GK1.5 is a rat mAb that recognizes the mouse CD4 Ag. It has been shown to deplete CD4+ cells in vivo and to be immunosuppressive. To evaluate the effect of the C region of this antibody in achieving cell depletion, chimeric antibodies, each having the rat GK1.5 V regions and one of the four mouse IgG C region isotypes, were compared with the native rat antibody. The chimeric antibodies and the native antibody were tested for their ability to mediate in vitro C-dependent cytotoxicity, in vivo cell depletion, and prolongation of allogeneic skin graft survival and suppression of alloantibody production. In vitro C-dependent cytotoxicity assays revealed that rat IgG2b and the chimeric antibodies containing mouse IgG2a, mouse IgG2b, and mouse IgG3 were effective in lysing CD4+ lymphocytes whereas mouse IgG1 was ineffective. In vivo studies of CD4+ cell depletion showed that mouse IgG2a, rat IgG2b, and mouse IgG2b were effective isotypes, mouse IgG1 was less effective, and mouse IgG3 did not deplete CD4+ cells. A correlation was found between the ability of an isotype to deplete CD4+ cells in vivo and its ability to prolong the survival of skin allografts and to suppress alloantibody production. The nondepleting mouse IgG3 was ineffective in these assays. Overall the most effective mouse isotype was IgG2a which was as effective as rat IgG2b. These results indicate 1) that syngeneic isotypes of mAb can cause cell depletion and consequently the prolongation of allograft rejection and suppression of alloantibody production; 2) that not all isotypes are equally effective; and 3) that the ability of a given isotype to deplete cells in vivo does not correlate with its ability to mediate C-dependent lysis in vitro. Our results are consistent with the hypothesis that in vivo depletion of cells is mediated by opsonization and binding through the FcR.

Animals↗
PubMed1992

The high-risk liver allograft recipient. Should allocation policy consider outcome?

The Boston Center for Liver Transplantation has accumulated one of the larger series of liver allograft recipients. This review has provided an opportunity to examine recent pronouncements by Medicare regarding patient selection and survival and to question whether the current allocation scheme best utilizes a scarce supply of donor liver allografts. Patients with primary biliary cirrhosis, sclerosing cholangitis, and metabolic derangements have enjoyed excellent survival: in aggregate, 78.9% at 1 year. In contrast, patients suffering from acute hepatic failure, patients requiring life support, or patients with primary graft failure who need a second liver transplant did poorly compared with other recipient groups: 45% 1-year survival. This center's experience reflects a more realistic expectation of patient survival because it considers the high-risk recipient by diagnosis and urgency status. This study also suggests that assessment of outcome should be a component of allocation planning in the future.

Adult↗
PubMed1992

Cellular mechanisms of rejection.

Studies by molecular biologists, protein chemists and cell biologists are rapidly providing new tools and information for those interested in the cellular mechanisms of graft rejection. Despite these contributions, a clear picture of the mechanisms involved in rejection has not yet evolved. However, whole new areas for research have developed, providing opportunities for new insights as well as therapeutic interventions.

Animals↗