摘要:

In the past, tolerance mechanisms have focused on processes that involve elimination (deletion) or paralysis (anergy) of immune responses. It is now becoming clearer that peripheral tolerance to antigen depends on the generation of regulatory cells that function to maintain the tolerant state. The development of peripheral tolerance may require that the immune system utilize several strategies, including deletion, anergy, and immunoregulatory pathways, and these strategies may overlap. Recent investigations using animal models of transplantation tolerance have demonstrated that immunoregulatory CD4 mechanisms may play a central role in limiting organ-destructive immune responses. In this Overview, we discuss the rationale behind the need for invoking active regulatory mechanisms in peripheral immunologic tolerance and summarize the data that support or refute a CD4 regulatory mechanism.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

An important consideration in application of hepatocyte transplantation is whether the number of engrafted hepatocytes is sufficient to achieve the desired effect. Here we have evaluated the proliferative potential of transplanted primary hepatocytes during regeneration of hepatic lobes. Two million hepatocytes isolated from congeneic normal Wistar-RHA rats were injected into the main portal vein of deficient, jaundiced Gunn rats. The right branch of the portal vein was ligated 24 hr before hepatocyte transplantation (group A) or transiently clamped during hepatocyte injection (group B) or 24 hr after hepatocyte injection (group C). In these groups, the three lobes supplied by the right branch of the portal vein rapidly atrophied and disappeared in 4 days, whereas the remaining lobes proliferated, as shown by size increase and 5-bromo-2-deoxy-uridine uptake. Two control groups received 2 million (group D) or 20 million hepatocytes (group E) without ligation. Hepatocyte engraftment occurred in all groups. The greatest hypobilirubinemic effect was observed in group A, in which serum bilirubin concentrations were reduced to 1.7±0.45 mg/dl from pretransplantation levels of 6.9±1.2 mg/dl. This effect was even greater than that observed after transplantation of 20 times more hepatocytes without ligation (group E). Specific endonuclease digestion of a polymerase chain reaction-amplified segment of theugt1gene from hepatic DNA showed that up to 25% of the DNA was of donor origin. This paralleled the hepatic bilirubin-UDP-glucuronosyl-transferase activity, which was above 50% of normal. The results indicate that the transplanted hepatocytes proliferate preferentially within the regenerating lobes, replacing more than 20% of the liver mass with the progency of the transplanted phenotypically normal hepatocytes.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.A synthetic peptide corresponding to residues 75-84 of the α1domain of HLA-B7 molecule (HLA-B7.75-84 [Allotrap]) inhibits cytotoxic T cell function in vitro and, when combined with subtherapeutic doses of cyclosporine (CsA), prolongs allogeneic cardiac survival. We now report the effects of HLA-B7.75-84 in the Lewis → Fischer 344 rat model of chronic cardiac allograft rejection.Methods.Animals were treated with CsA (5 mg/kg/day s.c.) alone or with CsA plus alternate-day HLA-B7.75-84 (20 mg/kg/day i.p.) for 30 days. Allografts harvested at day 100 were evaluated by histology and immunohistology.Results.HLA-B7.75-84 plus CsA prolonged allograft survival (75% of allografts survived >90 days) compared with CsA alone (27% of allografts survived >90 days) (P<0.05). Histologic examination of control allografts showed dense cellular infiltrates and moderate transplant arteriosclerosis (>75% of arteries showed 10-20% occlusion). Infiltrating leukocytes consisted of macrophages (>75% cells), T cells (10-20%), and rare natural killer cells (<5%). Cell activation was shown by expression of major histocompatibility complex class II antigens (>75%), interleukin (IL) 2 receptor (5-10%), and staining for IL-2 (≈5% of intragraft mononuclear cells), interferon-γ (5-10%) and tumor necrosis factor-α (≈20%). Leukocytes and vessels also showed labeling for the fibrogenic cytokine, transforming growth factor-β, and all vessels showed dense deposition of IgG (IgG2a, IgG2b) and C3. The addition of HLA-B7.75-84 decreased overall cellularity (P<0.01) without affecting the composition of the infiltrate, but completely prevented transplant arteriosclerosis, diminished myocardial injury, and abrogated expression of IL-2R, IL-2, interferon-γ, tumor necrosis factor-α, and transforming growth factor-β. HLA-B7.75-84 also blunted the humoral response, which resulted in a predominance of vascular deposition of the non-complement-fixing IgG2c isotype and a concomitant decrease in C3.Conclusions.Therapy with synthetic class I major histocompatibility complex peptide (HLA-B7.75-84) attenuates key histologic features of graft arteriosclerosis, in association with inhibition of multiple cytokines and growth factors and modulation of host alloantibody responses in vivo, which is of interest since Allotrap is currently undergoing clinical trials.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.Graft vessel disease is a special form of accelerated arteriosclerosis. Because immunological and nonimmunological factors can contribute to graft vessel disease, we developed a model that enables the study of both factors simultaneously.Methods.A carotid artery was allografted from DA to Lewis rats, with the excised native artery autografted on the contralateral side. Five groups of six to seven rats were treated for 8 weeks with vehicle (placebo) or cyclosporine (CsA) (0.3, 1, 3, and 10 mg·kg-1·day-1), which was administered using subcutaneous osmotic minipumps. The carotid lumen area was estimated in vivo at 2, 4, and 8 weeks by magnetic resonance imaging (MRI); CsA blood levels were determined twice. Carotid neointimal thickening and medial and luminal area were measured with histological techniques.Results.MRI showed bulging of the allografts but not autografts. Bulging disappeared over time with narrowing of the allograft lumina estimated by both MRI and histology. Histologically, vehicle-treated animals developed a massive neointima, which was inhibited in a dose-dependent manner by CsA. Autografts remained normal except for minimal subintimal thickening of two of four arteries in the group given the highest dose of CsA. Cellular rejection was detected in the allografts of all but the highest-dose group. The CsA blood levels were similar to those used in man at the two lower doses and about 10-fold higher at the highest dose.Conclusions.Subintimal thickening did not correlate with in vivo lumen size, a phenomenon that we have previously described for balloon catheter-induced lesions. CsA blood concentrations similar to those used in patients suppressed neointima formation in part, and 10-fold higher concentrations almost completely suppressed neointima formation.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.Large, anatomically discrete pancreatic islets, Brockmann bodies (BBs), exist in certain teleost fish. When transplanted under the renal capsules of streptozotocin-diabetic athymic nude mice, BB grafts produce uniform normoglycemia for 50 days and mammalian-like glucose tolerance profiles; however, these very discordant islets reject in 7-8 days when transplanted into euthymic BALB/c mice.Methods.In the present study, BBs were mass harvested, minced into <1-mm tissue fragments, and encapsulated in alginate-based macrospheres (5 mm diameter) or noodles (0.5×3 cm). Nonencapsulated and encapsulated BB fragments were transplanted intraperitoneally into streptozotocin-diabetic (nonfasting blood glucose >400 mg/dl) nu/nu and BALB/c mice. Glucose levels were monitored at least 3 times a week.Results.Encapsulated BB grafts uniformly survived >50 days (10/10) or >100 days (3/3) in nu/nu recipients. The mean graft survival time was 27±13 days in BALB/c recipients (n=7). Daily intraperitoneal administration of 2.5 mg/kg 15-deoxyspergualin, in combination with encapsulation, resulted in uniform long-term BB graft function in BALB/c recipients (n=5). Similarly, long-term function was achieved in four of six BALB/c recipients with daily intraperitoneal administration of 10 mg/kg cyclosporine (two grafts failed after 39 and 45 days). Nonencapsulated BB grafts transplanted intraperitoneally into BALB/c or nu/nu recipients functioned for <7 days; immunosuppression alone did not permit graft survival in BALB/c recipients. In all cases of graft survival of >50 days, grafts were surgically removed from the peritoneal cavity, and blood sugar levels returned to a diabetic state within a few days. Historical sections of grafts, stained with hematoxylin and eosin and immunoperoxidase for insulin, showed viable, well-granulated BB tissue.Conclusions.This study demonstrates that tilapia BBs are suitable for encapsulation and that encapsulated BBs can be made to function long term in diabetic mice.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.SDZ RAD is a new rapamycin analog with potent immunosuppressive activity. Compounds of the rapamycin class differ in their mode of action from cyclosporine, thus providing a rationale for potential synergism of these two potent immunosuppressants.Methods.The two-way mouse mixed lymphocyte reaction (BALB/c-CBA strain combination) was applied. Orthotopic kidney and heterotopic heart allografting was performed in the stringent DA-to-Lewis rat strain combination, with administration of compounds orally as microemulsion preconcentrate (i.e., Neoral in the case of cyclosporine).Results.Isobologram analysis of checkerboard titrations of SDZ RAD and cyclosporine in two-way mouse mixed lymphocyte reactions indicates a synergistic interaction in vitro. In vivo, the minimal effective dose of microemulsion cyclosporine giving long-term graft survival was 5.0 mg/kg/day; for SDZ RAD, the minimal effective dose was 5.0 mg/kg/day in kidney transplantation and >5.0 mg/kg/day in heart transplantation. Long-term allograft survival was noted for combinations of microemulsion cyclosporine administered at 1.0 or 2.0 mg/kg/day and SDZ RAD given at between 0.5 and 2.0 mg/kg/day. The index of synergy in different combinations ranged between 0.3 and 0.7.Conclusions.SDZ RAD and cyclosporine show synergism in immunosuppression, both in vitro and in vitro. They form a promising synergistic drug combination in allotransplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.This report describes the preclinical pharmacological profile of the new rapamycin analog, SDZ RAD, i.e., 40-O-(2-hydroxyethyl)-rapamycin.Methods.The pharmacological effects of SDZ RAD were assessed in a variety of in vitro and in vivo models, which included an autoimmune disease model as well as kidney and heart allotransplantation models using different rat strain combinations.Results.SDZ RAD has a mode of action that is different from that of cyclosporine or FK506. In contrast to the latter, SDZ RAD inhibits growth factor-driven cell proliferation in general, as demonstrated for the in vitro cell proliferation of a lymphoid cell line and of vascular smooth muscle cells. SDZ RAD is immunosuppressive in vitro as demonstrated by the inhibition of mouse and human mixed lymphocyte reactions and the inhibition of antigen-driven proliferation of human T-cell clones. The concentrations needed to achieve 50% inhibition in all of these assays fall into the subnanomolar range. SDZ RAD is effective in the in vivo models when given by the oral route in doses ranging between 1 mg/kg/day and 5 mg/kg/day. When compared with rapamycin, the in vitro activity of SDZ RAD is generally about two to three times lower; however, when administered orally, SDZ RAD is at least as active in vivo as rapamycin.Conclusions.In conclusion, SDZ RAD is a new, orally active rapamycin-derivative that is immunosuppressive and that efficiently prevents graft rejection in rat models of allotransplantation. SDZ RAD has therefore been selected for development for use in combination with cyclosporine A to prevent acute and chronic rejection after solid organ allotransplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.The mechanisms of corneal xenogeneic immunoreaction, as well as the potential role of immunosuppressive therapy in the suppression of corneal xenograft rejection, have not been thoroughly explored.Methods.BALB/c mice who received orthotopic corneal transplants (Lewis rats donors) were administered intraperitoneally anti-leukocyte function associated antigen-1 (LFA-1) monoclonal antibody (mAb) or FK506 (3 mg/kg/day) or both of these immunosuppressants during a 12-day postoperative period. Histological (hematoxylin-eosin stain) and immunohistochemical evaluations of enucleated eyes were performed. Humoral immune response and delayed-type hypersensitivity (ear-swelling assay) were evaluated.Results.The mean (±SD) graft survival time in the untreated control, FK506-treated, anti-LFA-1 mAb-treated, and combined-treatment groups was 5.8±0.8, 9.4±4.0, 8.7±5.0, and 67.7±16.4 days, respectively. In the untreated control group, mouse IgG, IgM, and C3 were expressed on the rat corneal grafts during the early postoperative phase. Flow cytometry studies revealed high titers of xenoreactive IgG and IgM antibodies. T helper 1 cytokines were expressed on xenografted corneal beds, and delayed-type hypersensitivity was induced. However, local expression of IgM, C3 and T helper 1 cytokines, serum antibodies of IgG and IgM, and delayed-type hypersensitivity were suppressed in the anti-LFA-1 mAb- plus FK506-treated group.Conclusions.Both humoral and cell-mediated immune reaction play an important role in the initial rejection in rat-to-mouse corneal xenotransplantation. The treatment with anti-LFA-1 mAb in combination with FK506 synergistically suppresses concordant corneal xenogeneic reaction.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.Graft-versus-host disease (GVHD) is a major complication after bone marrow transplantation, which may be refractory to immunosuppressive drugs. As preliminary case reports suggested that extracorporeal photochemotherapy (ECP) using a Therakos device might be beneficial, we conducted a pilot study to assess the efficacy and safety of a new ECP method that does not require administration of 8-methoxypsoralen (8-MOP) to the patient.Methods.ECP was performed three times a week for 3 weeks and then tapered according to the patient's course. Soluble 8-MOP was added ex vivo to an enriched mononuclear cell suspension obtained by a cell separator. This cellular suspension was then ultraviolet A irradiated and reinfused into the patient. Evaluation was performed using specific objective tests depending on clinical conditions.Results.The two patients in the study with acute GVHD and severe liver dysfunction resistant to steroid pulse showed no improvement with ECP treatment. The five patients with chronic GVHD (c-GVHD) had the following clinical features: three patients had myositis and two patients had severe cutaneous c-GVHD, including one patient with sclerodermoid lesions, one with bronchiolitis obliterans, one with bronchitis, and one with liver involvement. Immunosuppressive drugs were either prohibited or ineffective. The number of procedures for each patient ranged from 13 to 30. Cytapheresis required the use of a double-lumen catheter (4/5) or an arteriovenous fistula (1/5). No side effects were related to 8-MOP or ultraviolet A irradiation. Four of five patients improved after ECP; one patient with bronchiolitis obliterans, a fibrotic condition, remained stable.Conclusions.ECP treatment may be helpful for the treatment of severe c-GVHD and the avoidance of increased immunosuppression.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID