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At least 19 recordsLinked to original sources
PubMed1975

Immunologic enhancement of rat renal allografts. III. Immunopathologic lesions and rejection in long-surviving passively enhanced grafts.

Immunologic enhancement of renal allografts from (Lewis times Brown Norway) F1 to Lewis rats was achieved by administering a single dose of antidonor serum at the time of transplantation. A series of grafts functioning for 1 to 4 months after transplantation were examined by light and immunofluorescence microscopy to evaluate the long-term protective effects of the enhancing serum and to determine if previously unobserved lesions appeared in long survivors. Despite the absence of detectable circulating cytotoxic alloantibody, long-term allografts showed necrotizing glomerular and arterial lesions which resembled those seen in acutely rejecting grafts and were compatible with humoral rejection. Thus, in this model, there is a late decline in the ability of passive enhancement to inhibit humoral rejection. Long-term grafts also developed tubular lesions with deposition of immunoglobulin and complement on the tubular basement membranes (TBM). Anti-TBM antibodies were demonstrated in recipients' sera and found to be organ specific but not major histocompatibility antigen or species specific. This tubular lesion is therefore a unique form of allograft injury in which the immune response is directed against tissue antigen(s) which are distinct from the major histocompatibility antigens that induce rejection.

Animals↗
PubMed1986

Prolonged skin allograft survival through enhancement effects on donor tissue.

A skin allograft retransplantation model was utilized to study the mechanism of immunological enhancement in a murine system. Enhancement was accomplished by treating allografted recipients with host antidonor serum (B6AF1 anti-B10.D2 alloantiserum). Grafts from enhanced or untreated hosts were retransplanted after seven days onto a second recipient. Enhanced retransplanted grafts had significantly prolonged survival as compared with unenhanced grafts. The survival of enhanced retransplanted grafts was as prolonged as that of primary skin grafts on antiserum-treated hosts. Splenocytes harvested from recipients of enhanced retransplanted allografts showed delayed and diminished development of T cell responses to graft alloantigens. Sensitization of the second recipient abrogated prolonged survival of enhanced retransplanted grafts. Also, enhancement prevented sensitization of allografted recipients. One interpretation of these studies suggests that a sensitization block is a sufficient mechanism of skin allograft enhancement. The site of action of antisera is within the graft itself. Decreased T cell responses in the host are indirect effects of diminished antigenicity of enhanced grafts. Further studies of immunological enhancement should be directed to the graft, not toward the graft recipient.

Animals↗
PubMed1984

Effects of passive enhancement on graft and host. Graft adaptation by alloantibody as the mechanism of prolonged skin allograft survival.

The cellular response to passively enhanced allogeneic skin grafts in mice was investigated using alloantiserum raised in hyperimmunized (C57BL/6 X A/J)F1 (B6AF1) against B10.D2oSn (B10.D2) mice. B6AF1 mice given B10.D2 skin grafts and passively enhanced with B6AF1 anti-B10.D2 alloantiserum (anti-31) showed delayed development of the ability to generate high levels of specific cytotoxicity in vitro. This delayed responsiveness was not transferable in vivo to freshly skin grafted mice, nor could cell-mediated suppression of development of in vitro responses be demonstrated in mixing experiments. These results suggested that alloantiserum acted on the graft. When skin grafts from passively enhanced animals were transferred to naive recipients prolonged graft survival was seen. Our results suggest that the mechanism of prolonged graft survival of the passively enhanced murine skin graft was through alteration of inherent graft immunogenicity, rather than a direct effect on the host.

Animals↗
PubMed2000

Selective blockade of IL-15 by soluble IL-15 receptor alpha-chain enhances cardiac allograft survival.

IL-15 is a T cell growth factor that shares many functional similarities with IL-2 and has recently been shown to be present in tissue and organ allografts, leading to speculation that IL-15 may contribute to graft rejection. Here, we report on the in vivo use of an IL-15 antagonist, a soluble fragment of the murine IL-15R alpha-chain, to investigate the contribution of IL-15 to the rejection of fully vascularized cardiac allografts in a mouse experimental model. Administration of soluble fragment of the murine IL-15R alpha-chain (sIL-15Ralpha) to CBA/Ca (H-2k) recipients for 10 days completely prevented rejection of minor histocompatibility complex-mismatched B10.BR (H-2k) heart grafts (median survival time (MST) of >100 days vs MST of 10 days for control recipients) and led to a state of donor-specific immunologic tolerance. Treatment of CBA/Ca recipients with sIL-15Ralpha alone had only a modest effect on the survival of fully MHC-mismatched BALB/c (H-2d) heart grafts. However, administration of sIL-15Ralpha together with a single dose of a nondepleting anti-CD4 mAb (YTS 177.9) delayed mononuclear cell infiltration of the grafts and markedly prolonged graft survival (MST of 60 days vs MST of 20 days for treatment with anti-CD4 alone). Prolonged graft survival was accompanied in vitro by reduced proliferation and IFN-gamma production by spleen cells, whereas CTL and alloantibody levels were similar to those in animals given anti-CD4 mAb alone. These findings demonstrate that IL-15 plays an important role in the rejection of a vascularized organ allograft and that antagonists to IL-15 may be of therapeutic value in preventing allograft rejection.

Animals↗
PubMed1982

Immunogenicity of retransplanted rat kidney allografts. Effect of inducing chimerism in the first recipient and quantitative studies on immunosuppression of the second recipient.

It has been previously shown that long surviving, enhanced (AS X AUG)F1 rat kidneys residing in a primary AS recipient are not acutely rejected if transferred into a second AS recipient. The reduced immunogenicity of the retransplanted graft was attributed to a depletion of incompatible passenger cells. It is shown here that if the primary AS recipient is made chimeric by x irradiation and injection of (AS X AUG)F1 bone marrow cells, transfer of the long surviving, enhanced graft into a second AS recipient provokes acute graft rejection comparable to that observed when normal (AS X AUG)F1 kidneys are transplanted into untreated AS recipients. Transplantation of passenger cell-depleted AUG kidneys into AS recipients leads to graft rejection, with a median survival time of 22 d. Treatment of these recipients with as little as 1.5 mg/kg cyclophosphamide for 14 d induces prolonged graft survival. By contrast, five times as much cyclophosphamide treatment is required to induce prolonged survival of normal AUG kidneys (i.e., containing incompatible passenger cells) transplanted to AS recipients. These results confirm that the major alloimmunogenic stimulus of rat kidney grafts is provided by the incompatible passenger cells.

Animals↗
PubMed2000

Mechanisms of tolerance induction and prevention of cardiac allograft vasculopathy in miniature swine: the effect of augmentation of donor antigen load.

OBJECTIVE: Cotransplantation of a donor kidney along with a heart allograft can induce tolerance to both organs and prevent cardiac allograft vasculopathy in miniature swine. To determine whether the tolerogenic effect of donor kidney cotransplantation was due to an effect specific to the kidney graft or to an increase in donor antigen load, we compared heart-kidney recipients with recipients receiving two class I disparate hearts or with recipients receiving donor peripheral mononuclear cells at the time of isolated heart transplantation. METHODS: Recipients of major histocompatibility complex class I disparate allografts received 12 days of cyclosporine (INN: cyclosporin; 10-13 mg/kg administered intravenously on days 0-11). Group 1 animals received a heart alone (n = 5). Group 2 animals received heart and kidney allografts (n = 4). Group 3 animals received two major histocompatibility complex-matched heart allografts (n = 4). Two double-heart recipients were thymectomized 21 days before transplantation. Group 4 animals received a heart allograft and an infusion of high-dose donor peripheral blood leukocytes (2.5 x 10(9) cells/kg, n = 2). RESULTS: Vasculopathy developed in group 1 recipients and the allografts were rejected within 55 days. Group 2 recipients accepted their heart and kidney allografts indefinitely without vasculopathy. Euthymic recipients from group 3 accepted their hearts long-term (>190 and >197 days), but vascular lesions developed. In thymectomized recipients from group 3, the hearts were rejected in 63 and 96 days with severe vasculopathy. Group 4 recipients demonstrated transient macrochimerism but their hearts were rejected within 47 and 63 days. CONCLUSIONS: The beneficial effects of donor kidney cotransplantation on cardiac allograft survival and prevention of cardiac allograft vasculopathy are likely to involve both an increase in donor antigen load and an effect specific to the kidney allograft.

Animals↗
PubMed1981

Experimentally induced transplantation tolerance. I. Dissociation of effector lymphocytes specific for alloantigens by neonatal tolerance induction.

Neonatal tolerance was induced in CBA mice to alloantigens expressed by lymphoid cells of the A/Sn strain. 50% of the grafted animals maintained viable skin grafts for greater than 120 days and thus were considered operationally tolerant. However, splenic lymphocytes from these animals were capable of in vitro activation of DNA synthesis in response to the tolerizing alloantigens. Likewise, the spleen contained precursors of cytotoxic effector cells capable, upon activation, of similarly recognizing the major histocompatibility complex alloantigens used for tolerance induction. In contrast, in vivo graft-versus-host (GVH) effector function was absent, suggesting a possible dissociation of cells involved in the in vitro cell-mediated lympholysis and the in vivo GVH. Determination of potential serum-blocking factors as a possible mechanism of graft survival in these tolerant animals proved negative.

Animals↗
PubMed2002

Donor-lymphocyte infusion induces transplantation tolerance by activating systemic and graft-infiltrating double-negative regulatory T cells.

Donor-lymphocyte infusion (DLI) before transplantation can lead to specific tolerance to allografts in mice, nonhuman primates, and humans. We and others have demonstrated a role for regulatory T cells in DLI-induced, donor-specific transplantation tolerance, but it is not known how regulatory T cells are activated and where they execute their function. In this study, we observed, in both transgenic and normal mice, that DLI before transplantation is required for activation of alphabeta-T-cell-receptor-positive, CD3(+)CD4(-)CD8(-) double-negative (DN) regulatory T cells in the periphery of recipient mice. More interestingly, DLI induced DN regulatory T cells to migrate preferentially to donor-specific allogeneic skin grafts and to form a majority of graft-infiltrating T cells in accepted skin allografts. Furthermore, both recipient-derived peripheral and graft-infiltrating DN T cells were able to suppress and kill antidonor CD8(+) T cells in an antigen-specific manner. These data indicate that DLI may induce donor-specific transplantation tolerance by activating recipient DN regulatory T cells in the periphery and by promoting migration of regulatory T cells to donor-specific allogeneic skin grafts. Our results also show that DN regulatory T cells can eliminate antidonor T cells both systemically and locally, a finding suggesting that graft-infiltrating T cells can be beneficial to graft survival.

Animals↗
PubMed2000

Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: considerations for the allogeneic transplantation therapy of leukemia and lymphoma.

Allogeneic stem cell transplantation (SCT) represents a curative treatment option for patients with leukemia and lymphoma. T lymphocytes contained in the allograft mediate a graft-versus-leukemia (GVL) effect and prevent graft rejection; however, T cells also initiate graft-versus-host disease (GVHD). Identification of T cell populations which mediate a GVL effect and prevent rejection with reduced GVHD will likely improve transplantation outcome. T cells exist in four functionally-defined populations, the CD4+, Th1/Th2 and CD8+, Tc1/Tc2 subsets. Th1-type CD4 cells primarily secrete type I cytokines (IL-2 and IFN-gamma), whereas Th2 cells secrete type II cytokines (IL-4, IL-5, and IL-10). Similarly, the CD8+ Tc1 and Tc2 cells differentially secrete the type I and type II cytokines, respectively. In addition to cytokine secretion, Tc1 and Tc2 populations mediate cytolytic effects, with Tc1 cells utilizing both perforin- and fas-based killing pathways, whereas Tc2 cells primarily utilize perforin-mediated cytolysis. In murine transplantation models of graft rejection, GVHD, and GVL effects, we have evaluated such functional T cell subsets for their ability to differentially mediate and regulate transplantation responses. These studies demonstrate that donor Th2 cells do not initiate acute GVHD, and can regulate the GVHD mediated by unmanipulated donor T cells without impairing alloengraftment. Additional experiments have shown that allospecific donor Tc2 cells result in reduced GVHD, and mediate a significant GVL effect. Thirdly, we have demonstrated that non-host reactive Tc2 cells with veto-like activity can potently abrogate marrow rejection independent of GVHD. Together, these results demonstrate that functionally-defined donor Th2 and Tc2 populations play an important role in the regulation of GVHD, the prevention of graft rejection, and the mediation of GVL effects, and suggest that utilization of Th2 and Tc2 cells in clinical allogeneic SCT may have potential for improving treatment outcome.

Animals↗
PubMed1985

Long-term prolongation of cardiac allografts by subtherapeutic levels of cyclosporine in rats conditioned with pretransplant blood transfusions and cyclosporine.

This study was aimed at ascertaining whether long-term graft survival was achievable with short term cyclosporine (CsA) therapy or with subtherapeutic doses of CsA in rats conditioned with blood transfusions (BT) combined with CsA. Previous studies had shown that donor-specific transfusions combined with a short course of CsA interacted synergistically, resulting in considerable prolongations of ACI and BUF grafts in LEW hosts receiving no postoperative treatment. The donor-specific depression of alloreactivity was confirmed in the present study by showing a depression of mixed-lymphocyte reaction (MLR) reactivity as well as of humoral antidonor responses in BT-CsA conditioned rats. The effects of postoperative CsA were then studied in recipients conditioned with BT-CsA or BT alone. ACI and BUF cardiac graft survival in LEW hosts conditioned with BT and treated with a five-day postoperative course of CsA (20 mg/kg/day) were indistinguishable from graft survival in untransfused hosts (ACI: 35.6 +/- 15.5 vs. 38.8 +/- 7.4; BUF: 58.4 +/- 39.8 vs. 48.0 +/- 21.7) indicating no interaction between BT and CsA under these conditions. In contrast, the effect of a post-operative five-day course of CsA (10 mg/kg/day) was extended by conditioning the recipients with donor-specific BT and CsA (ACI:41.7 +/- 7.0 vs. 27.4 +/- 11.6; P less than 0.05). More remarkably, a thirty-day course of subtherapeutic doses of CsA (2.5 mg/kg/day) resulted in long-term prolongation (greater than 100 days) of ACI grafts in a large proportion of hosts conditioned with donor-specific BT and CsA, while the majority of controls conditioned with nonspecific BT and CsA or CsA alone rejected their grafts within three weeks (P less than 0.01). The possible mechanisms of this phenomenon are discussed.

Animals↗
PubMed1986

Prolongation of murine skin allograft survival by immunologic manipulation with anti-interleukin 2 receptor antibody.

Administration of a rat monoclonal antibody (M7/20) directed against the murine interleukin 2 (IL 2) receptor in combination with sublethal x-irradiation of the recipient significantly enhanced the survival of skin allografts, both when the grafts were MHC disparate from the hosts and when only minor histocompatibility differences were present compared with untreated controls. No prolongation in graft survival was seen with either treatment alone at the dose employed. M7/20 and x-ray-treated allograft recipients also displayed significantly decreased alloantigen-specific reactivity against donor-strain spleen cells in both delayed-type hypersensitivity and cytotoxicity assays. Thus, such combination treatment reduces expression of host immune reactivity against graft determinants by several criteria. This work provides additional evidence that monoclonal antibodies directed against the IL 2 receptor may be useful in clinical transplantation.

Animals↗
PubMed1983

[Specific and nonspecific effects of blood transfusion on heart graft survival in the rat].

We investigated the role of various blood-transfusions regimens including donor specific and third-party blood transfusions in rat heart transplantations. One ml donor blood (BN; RT1n) given to the recipients (Lew, RT1(1)) of (Lew.BN)F1 rats 7 days prior to grafting prolonged heart survival (24 +/- 8 vs 9.9 +/- 2.7 in control). Heart graft survival was much less when donor blood was given to recipients 1 month before grafting. There was no complementary effect between BT from donor and from third party blood or vice-versa. In addition, although donor blood prolonged graft survival (19.7 +/- 7.5 vs 9.9 +/- 2.7) when given the day of surgery, post surgery sequential BT from the donor (day 0-3-7 and 14 after transplantation) did not further increased survival (14 +/- 4.6). The effect of donor-BT was RT1a specific since third-party blood (1 ml) was ineffective (9.5 +/- 1) whereas 1 ml of congenic RT1n rat (Lew. 1 N) blood increases heart survival: 14 +/- 2.14 vs 9.9 +/- 2.2 in control animals. Although only 1 ml of donor blood enhanced specifically the heart allografts of the corresponding RT1 phenotype, weekly repeated third-party BT (n = 8) did also prolong graft survival (13.7 +/- 3.4) suggesting that aside from classical and powerful model of active RT1 specific effect of BT, a nonspecific, dose-related mechanism can occur.

Animals↗
PubMed1983

Active enhancement of rat cardiac allografts induced by donor specific semisoluble antigens.

Active enhancement was induced in inbred rats with cardiac allografts using semisoluble antigens. The optimal time of antigen pretreatment and optimal dose of semisoluble antigens were examined. The presence of serum blocking factors in the sera of rats having had allografts for a long time was examined with a macrophage migration inhibition test and lymphocyte microcytotoxicity assay. Since the blocking factors of macrophage migration inhibition were increasing on the 7th day, that day was determined to be the optimal time of antigen pretreatment. The mean survival time (MST) of cardiac allografts in untreated rats was 17.2 +/- 7.5 days. Semisoluble antigens were administered at 2 mg/kg body weight 7 days before the graft, 4 mg/kg 7 days before the graft and 2 mg/kg divided over three days, 15, 8 and 1 day before the graft, and the MSTs of cardiac allografts of rats receiving these treatments were 71.2 +/- 39.9, 62.6 +/- 42.2 and 79.3 +/- 31.0 days, respectively. The MST in each group of the treated rats was significantly longer than that of the control group (p less than 0.01). Rejection of the allograft, however, was accelerated in a group treated with 8 mg/kg 7 days before the graft (MST: 8.4 +/- 3.2 days). Serum blocking factors were detected in the sera of approximately half of the rats having cardiac allografts which survived a long time.

Animals↗
PubMed2000

Correlation between enhancement of graft-versus-leukemia effects following allogeneic bone marrow transplantation by rIL-2 and increased frequency of cytotoxic T-lymphocyte precursors in murine myeloid leukemia.

A model of mouse acute myeloid leukemia (mAML) was used to study the effector mechanism mediating the graft-versus-leukemia (GVL) effects in recipients of allogeneic bone marrow cells (BMC). mAML-bearing SJL/J (H-2s) mice were lethally irradiated and then transplanted with a mixture of BMC and spleen cells (SC) derived from normal syngeneic or allogeneic mice. To augment the GVL effect, recipients were injected intraperitoneally with recombinant human interleukin-2 (rIL-2) (1.2 x 10(5) IU) for 3 consecutive days, starting one day post BMC + SC transplantation. Spleen cells from treated recipients were adoptively transferred to untreated secondary SJL/J mice to test for the existence of residual tumor cells. All the secondary recipients of SC from mAML-bearing SJL/J mice rescued with syngeneic (SJL/J) or allogeneic (B10.S) BMC+SC (H-2s) differing at minor antigens of the histocompatibility complex (MiHC) developed leukemia and died. In sharp contrast, none of the secondary recipients of SC obtained from identical mAML-bearing mice rescued with B10.S BMC + SC but activated in vivo with IL-2 developed leukemia. Adoptive recipients of SC obtained from mAML-bearing recipients of major histocompatibility complex (MHC)-disparate (C57BL/6, H-2b) cells remained free of leukemia regardless of the use of rIL-2. In parallel with the in vivo findings, a 4-day in vitro exposure of splenocytes to 6 x 10(3) IU/ml rIL-2 resulted in a 5- to 20-fold increase in the frequency of alloreactive cytotoxic T-lymphocyte (CTL) precursors (CTLp) across MiHC and MHC barriers and a 2- to 6-fold increase in their cytotoxic activity. Our data suggest that augmentation of GVL effects by rIL-2 may be due to CTL activation by rIL-2, not excluding the potential beneficial role of rIL-2-activated allogeneic natural killer cells and MHC non-restricted killer cells. Cumulatively, our results suggest potentially beneficial effects of rIL-2, when used jointly with bone marrow transplantation or allogeneic cell therapy, on eradication of leukemia.

Animals↗
PubMed1983

Opposite effects of the synthetic immunomodulator, muramyl dipeptide, on rejection of mouse skin allografts.

The influence of muramyl dipeptide (N-acetylmuramyl-L-alanyl-D-isoglutamine) on the rejection of mouse skin allografts was investigated. While the 0.1-mg dose administered on days 7, 6, 5 prior to transplantation caused significant prolongation of the graft survival, the 0.5-mg dose administered on days 3, 2, 1 prior to transplantation resulted in remarkable augmentation of the graft rejection. The present results support the view that muramyl dipeptide can induce both stimulatory and suppressive immune mechanisms, depending on the treatment regimen.

Acetylmuramyl-Alanyl-Isoglutamine↗