摘要:

BALB/c mice primed with CAF1splenocytes during the neonatal stage developed A/J-specific tolerance with prolonged survival (>60 days) of A/J skin grafts. Mice failed to develop A/J-specific cytotoxicity, but rejected third-party skin grafts and generated appropriate third-party cytotoxic T cell responses. We demonstrated previously that graft acceptance was associated with enhanced interleukin (IL)-4 and diminished interferon [IFN]-γ tolerogen-specific cytokine production, whereas third-party graft rejection was associated with the opposite pattern of cytokine production. We now report that neonatal mice do not mount mixed lymphocyte reaction responses against A/J, but the mice contain a higher percentage of IL-4-producing cells that were characterized as CD4+Mel-14'cells. Although alloantigen priming of both neonatal and adult control mice expands the CD4+Mel-1410subset, CD4+Mel-1410cells from neonatal primed mice produce significantly higher levels of IL-4 and IL-10 and lower IFN-γ, whereas CD4+Mel-1410cells from adult primed mice produce mainly IFN-y. Moreover, enzyme-linked spot immuno-sorption analysis demonstrates that, compared with adult primed mice, neonatal primed mice contain more IL-4-producing CD4 cells and less IFN-γ-producing cells, which indicates that neonatal antigen exposure induces and expands alloreactive Th2 memory CD4 cells. The addition of neutralizing antibodies against IL-4 and BL-10 to primary MLR failed to recover IFN-γ by CD4+Mel-1410cells, but cells secreted IFN-γ after a second in vitro restimulation with tolerogen, which indicates that CD4 cells from neonatal tolerant mice have the capacity to differentiate into Th1 cells. In summary, neonatal tolerant mice contain higher ratios of Th2/Thl CD4 cells, and the Th2 cytokines function to maintain the ratio by inhibiting Thl differentiation.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Prevention of hyperacute xenograft rejection in the pig-to-primate combination has been accomplished by removal of natural antibodies, complement depletion with cobra venom factor, or prevention of C3 activation with the soluble complement inhibitor sCRl. Although these strategies effectively prevent hyperacute rejection, they do not address the relative contribution of early (C3a, C3b) versus late (C5a, C5b-9) activated complement components to xenogeneic organ damage. To better understand the role of the terminal complement components (C5a, C5b-9) in hyperacute rejection, an anti-human C5 mAb was developed and tested in an ex vivo model of cardiac xenograft rejection. In vitro studies demonstrated that the anti-C5 mAb effectively blocked C5 cleavage in a dose-dependent manner that resulted in complete inhibition of both C5a and C5b-9 generation. Addition of anti-C5 mAb to human blood used to perfuse a porcine heart prolonged normal sinus cardiac rhythm from a mean time of 25.2 min in hearts perfused with unmodified blood to 79,296, or >360 min when anti-C5 mAb was added to the blood at 50$mUg/ml,100$mUg/ml,or 200 fig/ml, respectively. In these experiments, activation of the classical complement pathway was completely inhibited. Hearts perfused with blood containing the highest concentration of anti-C5 mAb had no histologic evidence of hyperacute rejection and no deposition of C5b-9. These experiments suggest that the activated terminal complement components C5a and C5b-9, but not C3a or C3b, play a major role in tissue damage in this porcine-to-human model of hyperacute rejection. They also suggest that targeted inhibition of terminal complement activation by an-ti-C5 mAbs may be useful in clinical xenotransplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Natural anti-carbohydrate antibodies are central to hyperacute rejection in ABO-incompatible allotransplantation and in discordant xenotransplantation. ABO-incompatible rejection has been inhibited successfully using intravenous soluble carbohydrates as antibody inhibitors. The approach has been less successful previously in pig to primate xenotransplantation, where the necessary concentrations of a partial inhibitor (Galαl-6Glc) proved highly toxic. In this study, we have identified more effective inhibitors of the dominant human anti-pig antibodies that bind to the pentasaccharide Galαl-3Galβ1–4GlcNAcβ31–3Galβ31–4Glcβ31-. The inhibitors are the terminal disac-charide (Galαl-3Gal) and terminal trisaccharide (Galαl-3Galβ31–4GlcNAc) of the target pentasaccharide. Twelve sera (3 from each ABO blood group) were tested in 3 different assays: lymphocytotoxic, lymphocyte flow cytometry, and solid-phase antigen ELISA. Fifty percent to 75% inhibition of human IgG and IgM was achieved using the disaccharide and trisaccharide inhibitors in the range of 10–50 mM.Disaccharide (70 mM) was used to inhibit hyperacute thrombosis in pig kidneys perfused for 40 min with heparinized human AB whole blood. The disaccharide completely inhibited red cell occlusion of glomerular but not of intertubular capillaries, although there was residual platelet thrombus in glomeruli. Disaccharide and trisaccharide can, therefore, be

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

It has been shown that donor-specific tolerance to cardiac allografts can be induced by pretreating the prospective recipient with injections of donor spleno-cytes (intrathymically) and antilymphocyte serum (in-traperitoneally) weeks or days before the actual transplantation. This procedure, however, lacks clinical relevance in the case of cadaver donors due to the obligatory interval between the start of the tolerance induction protocol and transplantation. We have tried to devise a protocol in which this interval is eliminated, thus allowing allotransplantationsimultaneouslywith tolerance induction.Our results show that simultaneous cardiac allotransplantation and intrathymic tolerance induction by intrathymic injection of donor splenocytes and treatment with antilymphocyte serum is indeed possible in the PVG to AO high-responder rat strain combination, provided that low doses of cyclosporine are given intramuscularly on day 1, 2, and 3 after transplantation. As we now are able to combine the start of tolerance induction with the actual allotransplantation, this procedure may indeed have clinical potential.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Administration of liposome-encapsulated immunomodulating agents muramyl tripeptide phosphatidyl ethanolamine (LE-MTPPE) or interferon-γ (LE-IFN-γ), or co-encapsulated MTPPE and IFN-γ (LE-(MTPPE/ IFN-y)) resulted in a dramatic increase of the nonspecific antimicrobial resistance in mice, as shown before. This kind of treatment is especially of use in immunocompromised hosts who are prone to severe infections. Application of these immunomodulators might protect these patients, e.g., transplant recipients, from opportunistic infections. However, accelerated rejection of the graft, resulting from augmentation of the antimicrobial defense in a nonspecific way, has to be avoided

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

To assess the effect of sampling error on renal allograft biopsies, we determined the concordance of diagnoses between 2 biopsy samples from the same renal allograft and the frequency with which 1 biopsy sample would underdiagnose or lead to the under-treatment of acute rejection. Two core samples from the same allograft biopsy procedure were labeled as core A and core B and presented to both unblinded and blinded pathologists, and each pathologist independently assigned an acute and a chronic rejection grade. A set of clinical data with pertinent prebiopsy information was combined with either the core A or core B histopathological diagnosis and presented to 3 transplant nephrologists who made treatment recommendations for each combination. Two cores were obtained in 79 allograft biopsies. Core pairs differed by $gEl grade of acute rejection in 30% and 50% of cases for unblinded and blinded pathologist readings, respectively. Moderate or severe acute rejection would have been missed with a 1 core in 9.5% of cases, increasing to 25.6% if only biopsy pairs containing at least 1 reading of moderate or severe acute rejection are included. Therapy would have failed to be increased with a single core in 7.5% of cases, increasing to 10.5% if only pairs containing at least one recommendation of an increase in therapy are included. The use of 2 cores of renal allograft tissue provides better diagnostic information and thereby leads to appropriate increases in antirejection therapy without increasing the complication rate of the procedure.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The results of renal cadaver transplants performed between 1984 and 1994 and reported to the Collaborative Transplant Study were analyzed to examine the effect of rejection prophylaxis with OKT3. OKT3 prophylaxis with sequential (i.e., delayed) addition of cy-closporine (CsA), compared with immunosuppressive treatment that included CsA but not OKT3, resulted in a significantly higher overall 3-year graft survival rate in recipients of first transplants (75$pM1% vs. 71 $pM1%, respectively; PP<0.001). In contrast, the simultaneous administration of OKT3 and CsA from the first posttransplant day did not result in improved graft survival over treatment with CsA alone. Graft survival rates were significantly associated with matching for HLA-A, -B, and -DR antigens in both first and retransplant recipients treated with a sequential protocol of OKT3/CsA (P<0.01). Among patients with preformed panel reactive lymphocytotoxic antibodies >50%, significantly better 3-year graft survival rates were obtained with sequential OKT3/CsA than were achieved without OKT3 in first transplant recipients (80$pM5% vs. 63$pM1%, respectively;P<0.001) and in retransplant recipients (73$pM5% vs. 58$pM1%, respectively;P<0.01). Significantly improved 3-year graft survival rates with OKT3 and sequential CsA were likewise obtained in two other groups of high-risk patients: black recipients (P<0.001) and pediatric recipients (P<0.01). The results demonstrate an advantage for OKT3 prophylaxis in conjunction with delayed CsA therapy among renal transplant recipients at high immunological risk, particularly among presensitized patients.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Forty-five recipients of bone marrow from HLA-identical siblings were given intravenous immune globulin (IVIG) 0.5 g/kg once a week during the first 3 months after transplantation. Fifty-three consecutive previously transplanted HLA-identical siblings were included as controls. Only patients who were cytomegalovirus (CMV) seropositive or had a CMV-seropositive donor were included. There were no major differences in patient characteristics between the two groups. However, more patients in the IVIG group received individualized graft-versus-host disease (GVHD) prophylaxis with less cyclosporine (P<0.01), more controls received liposomal amphotericin B (P=0.01), and more patients in the IVIG group received low-dose heparin as prophylaxis against veno-occlusive disease of the liver (P<0.001). Median follow-up was 21 months in the IVIG group and 47 months in the control group. There were no differences between the groups with regard to time to engraftment, hospitalization time, or days with fever. No differences between the IVIG group and control group were detected in the incidence of acute GVHD grade II-IV (17% vs. 23%) or chronic GVHD (30% vs. 42%). The incidence of bacterial septicemias (53% vs. 63%) and invasive fungal infections (9% vs. 6%) was unaffected by IVIG treatment. The incidence of symptomatic CMV infection was the same in the two groups (14% vs. 16%). One control patient died of CMV interstitial pneumonitis, and 1 patient from each group died from viral interstitial pneumonitis of other origin. The incidence of veno-occlusive disease (VOD) was 16% in the IVIG group versus 6% in the controls (P=NS). Fatal VOD occurred in 11% of the IVIG group compared with none of the controls (P=0.02). Other transplant-related complications did not differ between the two groups. Two-year survival was 62% in the IVIG group and 60% in the controls (P=NS). No significant beneficial effect was seen with IVIG, which may increase mortality in VOD. The use of high dose IVIG as prophylaxis in marrow transplant recipients is questioned.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Intestinal graft-versus-host disease (GVHD) causes anorexia, vomiting, abdominal pain, and diarrhea. We investigated oral beclomethasone dipropionate (BDP), a potent, topically active corticosteroid, as therapy for this disease. Forty-two allogeneic marrow-graft recipients with biopsy-proven intestinal graft-versus-host disease of mild-to-moderate severity received BDP (8 mg daily) for up to 28 days. Weekly symptom scores, oral intake, and surveillance throat and stool cultures were compared with baseline values. Adrenal testing was performed serially in patients not receiving concurrent prednisone. Improvement was seen in appetite (P<0.001), oral intake (P<0.001), nausea (P=0.013), and diarrhea (P=0.02) over the course of therapy, and an overall beneficial response was observed in 72% of 40 evaluable patients. Surveillance cultures of throat and stool showed no increase in bacterial or fungal colonization over time. The adrenal axis became suppressed in 11 of 20 evaluable patients (55%) but suppression was not a prerequisite for clinical response, as 6 of 9 patients who retained normal adrenal function improved clinically. We conclude that oral BDP is a safe and effective treatment for mild-to-moderate intestinal graft-versus-host disease. Systemic absorption probably occurs, but adrenal suppression is not a prerequisite for clinical efficacy, suggesting that the biological effect is primarily topical. BDP should be further investigated as a topical therapy for intestinal GVHD.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Due to the accumulation of evidence concerning a putative role of nitric oxide (NO) in graft-versus-host disease (GVHD), we performed follow-up measurements of the stable end-products of NO, nitrite/nitrate (NO2-/NO3-) in plasma of patients undergoing allogeneic (n=16) and autologous (n=6, as a control) bone marrow transplantation. NO2-/NO3-concentrations were set in relation to the clinical course and to serum levels of soluble tumor necrosis factor receptor 75 (sT-NFrec 75) and neopterin, both of which are known to be sensitive indicators of cellular immune activation phenomena involving macrophages in vivo, and endogenous interleukin (IL)-10, a major T helper cell type 2 (TH-2)-derived cytokine and potent inhibitor of macrophage activation and NO formation.A significant rise of NO2-/NO3-levels was observed in patients with GVHD and preceded the onset of clinical symptoms by up to 3 days. In contrast to indicators of macrophage activation, i.e., neopterin and sT-NFrec75, NO2-/NO3-concentrations were not significantly altered from baseline levels during infectious complications, as NO2-/NO3-concentrations did not fluctuate in patients after autologous engraftment. During episodes of acute GVHD, NO2-/NO3-concentrations showed a strong positive correlation with levels of plasma neopterin and sTNFrec 75, but were also significantly related to IL-10. In non-GVHD patients, a negative correlation between IL-10 and NO2-/NO3-concentrations was evident.Therefore, NO2-/NO3-determination may be a valuable early indicator of the initiation of human GVHD. Our results provide some further insights concerning cytokine-related metabolic changes in the course of human GVHD in vivo which may prove useful in the development of new therapeutic approaches for this disease.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID