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M Waer

Publications and source records attributed to M Waer.

At least 19 recordsLinked to original sources
PubMed2003

Prevention of primary non-function of islet xenografts in autoimmune diabetic NOD mice by anti-inflammatory agents.

AIMS/HYPOTHESIS: High levels of inflammation locally in the graft during the initial days after transplantation can cause primary non-function (PNF) of grafted xenogeneic islets in NOD mice. The aim of this study was to explore in a model of spontaneous diabetes, the NOD mouse, the potential of anti-inflammatory agents in the prevention of PNF after xenogeneic islet transplantation. METHODS: Spontaneously diabetic NOD mice were transplanted with 300 rat islets. Animals were treated with acetylsalicylic acid (AsA), rofecoxib, TGF-beta or IL-1 receptor antagonist (IL-1ra). Intra-graft expression of inflammation-related molecules was measured by real time PCR 8 h post-transplantation. At the same time point, plasma nitrite levels were measured. RESULTS: Xenogeneic islets transplanted in control spontaneously diabetic mice resulted in PNF in 16 out of 38 mice (42%). Initial graft loss was not altered by administration of rofecoxib (30%) or TGF-beta (25%). AsA reduced the rate of rapid graft loss to 8% ( p<0.05 vs controls) and administration of IL-1ra even totally prevented PNF (0%, p<0.05 vs controls). Furthermore, all therapies prolonged the mean survival time of xenogeneic islet grafts. The inhibition of PNF by AsA was associated with decreased intra-islet levels of inflammation-related molecules (IL-1, TNF-alpha, iNOS, COX-2) and chemokines (MCP-1 and MIP-3alpha). Finally, also a diminished production of systemic nitrite levels was observed in AsA- and IL-1ra-treated islet recipients. CONCLUSIONS/INTERPRETATION: These data show that treatment with AsA or IL-1ra prevents PNF after islet transplantation in spontaneously diabetic NOD mice. Moreover, the involvement of non-specific inflammation is recognized in xenogeneic islet PNF in spontaneously diabetic NOD mice.

Animals↗
PubMed2003

Break of tolerance via donor-specific blood transfusion by high doses of steroids: a differential effect after intestinal transplantation and heart transplantation.

UNLABELLED: Tolerance requires active mechanisms. How immunosuppressors affects tolerance is poorly understood. METHODS: RA (RT1(p))/PVG (RT1(c)) rats were used as donor/recipient. Intestinal and heart transplant model were selected as highly and poorly immunogenic organs. Studied groups were 1, rejecting control; 2, received peritransplant steroids; 3, donor-specific blood transfusion (DSBT); 4, DSBT plus peritransplant steroids; and 5, DSBT+periDSBT Ste. RESULTS: Intestinal transplant recipients in group 1 died on posttransplant day (d) 18. In group 2, steroids did not change survival (17 days, P >.05 versus group 1). With DSBT (group 3), all rats survived >75 days, whereas with steroids those in group 4 survived 59 days (P >.05 vs group 3) and group 5 survived 51 days (P <.05 versus group 3). Survivors in group 2 were tolerant as evidenced by acceptance of secondary donor-specific (not third-party) graft. However, 100% and 33% of donor-specific secondary grafts were rejected in groups 4 and 5 (P <.05 and P >.05 versus group 3). In heart transplants, steroid treatment had no effect on graft survival (group 1 9 days; group 2 9 days; P >.05). DSBT (group 3) induced 100% tolerance (primary: >100 days, secondary: 100%). Unlike in intestinal transplantation, adjunction peritransplant steroids (group 4) allowed 100% of primary and 83% of secondary graft acceptance (P >.05 versus group 3). In group 5, (DSBT+periDSBT steroids) acceptance of primary and secondary grafts tended to be reduced (primary: 77 days; P >.05 versus group 3; secondary: 67%, P >.05 versus group 3). CONCLUSION: Steroid induction did not prolong graft survival after either intestinal or heart transplant. Adjunction of steroids to a DSBT tolerogenic regimen caused rejection of primary and secondary grafts, particularly after intestinal transplantation. Routine use of steroids in the clinics must be reconsidered, particularly when immunogenic organs are transplanted and when immunomodulation is applied.

Animals↗
PubMed2002

Treatment of autoimmune diabetes recurrence in non-obese diabetic mice by mouse interferon-beta in combination with an analogue of 1alpha,25-dihydroxyvitamin-D3.

Autoimmune diabetes recurrence is in part responsible for islet graft destruction in type 1 diabetic individuals. The aim of the present study was to design treatment modalities able to prevent autoimmune diabetes recurrence after islet transplantation in spontaneously diabetic NOD mice. In order to avoid confusion between autoimmune diabetes recurrence and allograft rejection, we performed syngeneic islet transplantations in spontaneously diabetic NOD mice. Mice were treated with mouse interferon-beta (IFN-beta, 1 x 105 IU/day), a new 14-epi-1,25-(OH)2D3-analogue (TX 527, 5 microg/kg/day) and cyclosporin A (CsA, 7.5 mg/kg/day) as single substances and in combinations. Treatment was stopped either 20 days (IFN-beta and CsA) or 30 days (TX 527) after transplantation. Autoimmune diabetes recurred in 100% of control mice (MST 11 days). None of the mono-therapies significantly prolonged islet graft survival. Combining CsA with TX 527 maintained graft function in 67% of recipients as long as treatment was given (MST 31 days, P < 0.01 versus controls). Interestingly, 100% of the IFN-beta plus TX 527-treated mice had normal blood glucose levels during treatment, and even had a more pronounced prolongation of graft survival (MST 62 days, P < 0.005 versus controls). Cytokine mRNA analysis of the grafts 6 days after transplantation revealed a significant decrease in IL-2, IFN-gamma and IL-12 messages in both IFN-beta plus TX 527- and CsA plus TX 527-treated mice, while only in the IFN-beta with TX 527 group were higher levels of IL-10 transcripts observed. Therefore, we conclude that a combination of IFN-beta and TX 527 delays autoimmune diabetes recurrence in islet grafts in spontaneously diabetic NOD mice.

Alkynes↗
PubMed2001

Transplantation tolerance and autoimmunity after xenogeneic thymus transplantation.

Successful grafting of vascularized xenografts (Xgs) depends on the ability to reliably induce both T cell-independent and -dependent immune tolerance. After temporary NK cell depletion, B cell suppression, and pretransplant infusion of donor Ags, athymic rats simultaneously transplanted with hamster heart and thymus Xgs developed immunocompetent rat-derived T cells that tolerated the hamster Xgs but provoked multiple-organ autoimmunity. The autoimmune syndrome was probably due to an insufficient development of tolerance for some rat organs; for example, it led to thyroiditis in the recipient rat thyroid, but not in simultaneously transplanted donor hamster thyroid. Moreover, grafting a mixed hamster/rat thymic epithelial cell graft could prevent the autoimmune syndrome. These experiments indicate that host-type thymic epithelial cells may be essential for the establishment of complete self-tolerance and that mixed host/donor thymus grafts may induce T cell xenotolerance while maintaining self-tolerance in the recipient.

Animals↗
PubMed2001

Transforming growth factor-beta inhibits lymphokine activated killer cytotoxicity of bone marrow cells: implications for the graft-versus-leukemia effect in irradiation allogeneic bone marrow chimeras.

BACKGROUND: We have previously shown that allogeneic bone marrow (BM) chimeras preconditioned with total lymphoid irradiation and low-dose total body irradiation (TLI/TBI) develop a stronger graft-versus-leukemia (GVL) effect than chimeras preconditioned with high-dose total body irradiation only (TBI). Here, we report on the possible role of cytokines in the mechanism underlying this GVL effect. METHODS: Splenic mRNA levels of the cytokines interleukin (IL)-1, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-15, interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta (TGF-beta), and of inducible nitric oxide synthetase were determined by reverse transcription-polymerase chain reaction in TLI/TBI- or TBI-conditioned C3H/AKR BM chimeras challenged with AKR-type BW5147.3 leukemia cells. Ex vivo TGF-beta protein production by splenocytes was determined using ELISA. The possibility that cytokines influence the GVL effect by modulating the activity of IL-2-activated lymphocytes (LAK cells) was investigated by in vitro assays on donor-type BM cells. RESULTS: Of all cytokine mRNA levels studied, those of TGF-beta and IL-7 were different between groups; both were significantly more elevated in TBI- than in TLI/ TBI-conditioned or normal mice. Differences were apparent after conditioning and were not influenced by additionally injected BM or leukemia cells. Cultured splenocytes of TBI-conditioned animals produced significantly more TGF-beta protein than those of TLI/TBI-conditioned ones or normal controls. r-TGF-beta but not r-IL-7 suppressed in vitro LAK activity of donor-type BM cells against BW5147.3 cells in a dose-dependent way. CONCLUSIONS: High-dose TBI-induced, host-derived splenic TGF-beta may inhibit generation of LAK cells from subsequently transplanted donor BM cells, suppressing their capacity to generate cytotoxicity upon injection of leukemia cells. The cytokine profile, induced by irradiation in host hematopoietic organs, can significantly modify posttransplant immunological processes such as the GVL effect and graft-versus-host disease (GVHD).

Animals↗
PubMed2001

Psychometric properties of the "Modified Transplant Symptom Occurrence and Symptom Distress Scale".

The aim of this study was to assess key aspects of the reliability and validity of the "Modified Transplant Symptom Occurrence and Distress Scale," an instrument measuring symptom experience associated with side effects of triple drug therapy in transplant patients. This cross-sectional, comparative study included 108 renal transplant recipients (61% men; 39% women) with a median age of 47 years and a median posttransplant status of 5.5 years. Renal transplant patients were matched by age and gender with 108 healthy control persons not taking immunosuppressive drugs. Content validity, construct validity and discriminant validity of the instrument were substantiated. Internal consistency reliability was not useful to assess in this instrument, as the conditions for calculating Cronbach's alpha were not satisfied. These findings document the validity of the "Modified Transplant Symptom Occurrence and Symptom Distress Scale" as an instrument to measure symptom experience with immunosuppressive drugs.

Anti-Inflammatory Agents↗
PubMed2000

Graft-versus-leukemia effect in minor antigen mismatched chimeras given delayed donor leucocyte infusion: immunoregulatory aspects and role of donor T and ASGM1-positive cells.

BACKGROUND: Previous studies have demonstrated that delayed donor leukocyte infusion (DLI) can increase graft-versus-leukemia (GVL) without increasing graft-versus-host-disease (GVHD) in MHC mismatched bone marrow (BM) chimeras. In our report, the immune status of minor antigen mismatched BM chimeras given DLI was studied. Particularly the role of donor ASGM1 positive or T cells in the graft-versus-leukemia effect (GVL) was investigated. METHODS: AKR mice (H2k, Mls1a, Thy1.1) received TBI (9,5 Gy) and T cell-depleted (TCD) C3H (H2k, Mls2a, Thy1.2) BM alone (BM chimeras), or TCD BM together with immunocompetent C3H spleen cells at the time of BM transplantation (BM+SP chimeras), or TCD BM and 3 weeks later C3H spleen cells (DLI chimeras). Chimerism and T lymphocyte subsets were scored using FACS and anti-Thy, anti-Vbeta6, anti-IL2-beta receptor, anti-CD4, anti-CD3, and anti-CD8 mAbs. Leukemia challenge consisted of 5 x 10(6) AKR T cell lymphoma (BW4157) cells injected i.v. ASGM1 positive (ASGM1+) cells and T cells were depleted using anti-ASGM1 or anti-Thy1.2 antibodies, respectively. Immune tolerance was studied using MLR and CML tests. RESULTS: BM + SP chimeras developed acute and lethal GVHD, whereas DLI chimeras were totally free from GVHD. In DLI chimeras, host-reactive cytotoxic T cells (CTL) could not be induced and host-reactive CD8Vbeta6 cells were deleted whereas CD4Vbeta6 cells and MLR reactivity persisted temporarily. In contrast, in BM+SP chimeras, anti-host CTL were easily generated and an expansion of both host-reactive CD8Vbeta6 and CD4Vbeta6 T cells was found as well as high anti-host MLR reactivity. Depletion of either ASGM1 + cells or T cells from the DLI inoculum resulted in an abrogation of GVL reactivity, suggesting that both cell populations were involved in the protection against BW4157 leukemia. Three weeks after DLI, the GVL effect waned which correlated with the disappearance of host-reactive CD4 cells and MLR reactivity. CONCLUSION: In minor antigen mismatched BM chimeras, anti-host reactivity after DLI is characterized by (1) an absence of clinical GVHD, (2) clonal deletion of host-reactive CD8 cells, (3) an absence of anti-host CTL induction, and ( 4) a temporary persistence of host-reactive CD4 T cells and of MLR reactivity. In addition, either donor ASGM1+ cells or an interaction between these cells and T cells contribute to the GVL effect.

Animals↗
PubMed2000

Natural killer cell- and macrophage mediated discordant guinea pig-->rat xenograft rejection in the absence of complement, xenoantibody and T cell immunity.

BACKGROUND: The role of natural killer (NK) cells and macrophages (Møs) in the absence of T cell immunity in discordant xenograft (xg) rejection was investigated. METHODS: Guinea pig hearts were transplanted into athymic nude rats receiving no treatment or antixenoantibody (xAb), anticomplement (C), antinatural killer (NK) cell therapy (antiasialo GM1 [anti-ASGM1]) or their combinations. For anti-xAb therapy, natural xAbs were absorbed/neutralized by pretransplant guinea pig blood transfusion (pGPBT), followed by administration of the malononitriloamide MNA715. Cobra venom factor (CVF) was administered as anti-C therapy. FACScan analysis and a standard cytotoxicity assay determined NK cell number and cytotoxicity, respectively. ELISA and the CH50 assay measured titers of xAb and C activity, respectively. Rejected Xgs were examined by light microscopy and by immunohistochemistry. RESULTS: All hyperacutely (15+/-4 min) rejected Xgs from untreated rats showed deposits of C3 and IgM without cellular infiltrates. Combined anti-xAb and anti-C (pGPBT/MNA715/CVF) treatment significantly prolonged the survival of Xgs (3.7+/-0.6 days, P<0.001 vs. control group) showing NK cell and Mø infiltration without deposition of xAbs or C3. NK cell depletion (day -12) followed by exposure of recovering NK cells to the guinea pig antigens failed to induce specific NK cell nonresponsiveness and to further prolong xg survival in combined anti-xAb/anti-C group. In contrast, adding of continuous and repetitive depletion of NK cells significantly further prolonged xg survival to 7.4+/-0.5 days (P<0,001 vs. the anti-xAb/anti-C group) with rejected Xgs densely infiltrated by activated Møs without involvement of NK cells, C or xAbs. CONCLUSIONS: When xAb and C are suppressed in the discordant guinea pig-into-nude rat model, NK cells play an important role in xg rejection. When also NK cells are suppressed, activated Møs seem to reject discordant Xgs. The induction of specific NK cell nonresponsiveness fails in the guinea pig-into-rat combination.

Animals↗
PubMed2000

Analogs of 1,25-dihydroxyvitamin D3 as dose-reducing agents for classical immunosuppressants.

BACKGROUND: Most immunosuppressants have a narrow margin between efficacy and side effects. A major goal in the development of immunomodulatory strategies is the discovery of combinations of drugs exerting synergistic immunomodulatory effects. The active form of vitamin D, 1,25(OH)2D3, is an immunomodulator that interacts with T cells but mainly targets antigen-presenting cells. We have demonstrated synergism between 1,25(OH)2D3 and cyclosporine, rapamycin, and FK506. The aim of this study was to investigate whether this synergism could be observed with other immunosuppressants (mycophenolate mofetil, leflunomide, and the methylxanthine A802715) and whether analogs of 1,25(OH)2D3 share this synergistic capacity in vivo. METHODS: In vitro, the median effect analysis was applied to the inhibition of phytohemagglutinin A-induced lymphocyte proliferation. In vivo, synergism between analogs of 1,25(OH)2D3 and cyclosporine or mycophenolate mofetil was evaluated in experimental autoimmune encephalomyelitis. RESULTS: In vitro, all combinations with 1,25(OH)2D3 were synergistic. The strongest synergism was seen with the inhibitors of interleukin 2 secretion, cyclosporine and FK506 (indexes 0.16 and 0.27, respectively). The weakest synergism was observed in combinations using A802715, a second-signal inhibitor (index 0.52), or the nucleotide synthesis inhibitor mycophenolate mofetil (index 0.43). In vivo, analogs of 1,25(OH)2D3 share the in vitro-observed synergism with 1,25(OH)2D3. Moreover, the differences in synergism with different immunomodulators were also present in vivo, where the best synergism was again seen in combination with cyclosporine (up to 100% paralysis protection). CONCLUSIONS: These data confirm that 1,25(OH)2D3 and its analogs are potent dose-reducing drugs for other immunomodulators, making them potentially interesting for clinical use in autoimmunity and transplantation.

Animals↗
PubMed2000

Immunomodulatory effects of pretransplant donor blood transfusion on T-cell-independent xenoreactive immunity.

BACKGROUND: Pretransplant blood transfusions have beneficial effects on both clinical and experimental allograft survival. In the present study, we examined whether pretransplant hamster blood transfusions (pHBT) alone or together with peritransfusion immunosuppressive strategies designed to target B cells and/or natural killer (NK) cells, could modulate T cell-independent (T-I) xenoreactivity in athymic nude rats. METHODS: Hamster or mouse hearts were heterotopically xenotransplanted into untreated or treated athymic nude rats receiving either pHBT, anti-B cell or anti-NK cell therapy alone or their combinations. Xenoreactive antibodies (xAbs) and the percentage of NK cells were analyzed by FACScan analysis. NK cytotoxicity was measured by a standard 4 hr 51Cr release assay. Xenografts (Xgs) were examined by hematoxylin-eosin (H&E), by light microscopic method with Masson's trichrome and orcein staining, by immunofluorescent staining for immunoglobulin M and C3 deposition, and by immunohistochemical staining for infiltration of NK cells and macrophages (Mphis). RESULTS: In 1 of 6 rats given pHBT alone 2 weeks before receiving hamster xenografts, Xg survival was prolonged to 55 days compared with 3.0+/-1.2 days in the other 5 animals and with 3.0+/-0.6 days in untreated animals. In the 55 days, surviving Xg infiltration of Mphis and NK cells was seen together with severe signs of chronic rejection, such as fibrosis and obliterative vasculopathy. The addition of the anti-B cell immunosuppressant MNA715 (malononitriloamide x920715, 20 mg/kg/day) from day -14 to day +14 or of 100 microL of rabbit anti-asialo GM1 serum ([anti-ASGM1] an NK cell depleting antibody) on day -14 resulted in a significant and species-specific prolongation of the survival of hamster Xgs, respectively 59.8+/-9.6 days and 58.2+/-14.7 days (P<0.001 vs. control group), but not of mouse heart Xgs that were rejected in a normal tempo. All prolonged hamster Xgs were infiltrated with Mphis and NK cells and developed severe lesions of chronic rejection, such as fibrosis and obliterative vasculopathy. In contrast, MNA715 or anti-ASGM1 alone had no effect on Xg survival (4.8+/-1.7 days and 2.7+/-0.6 days, respectively). Combined MNA715/anti-ASGM1 treatment only moderately promoted Xg survival (10+/-5.0 days; P<0.001). A simultaneous administration of pHBT, MNA715, and anti-ASGM1 induced indefinite and species-specific Xg survival in all recipients. In vivo and in vitro studies demonstrated that both T-I B cell and NK cell species-specific xenotolerance were achieved. CONCLUSIONS: Pretransplant blood transfusion may have a species-specific immunomodulatory effect on T-I xenoreactivity. This effect is further enhanced by a temporary co-administration of MNA715 or by a single injection of anti-ASGM1. A combination of pHBT, MNA715, and anti-ASGM1 induces species-specific T-I xenotolerance.

Animals↗