Intragraft cellular events associated with tolerance in pig allografts: The “acceptance reaction” (original) (raw)
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Journal of the American Society of Nephrology : JASN, 2000
Inbred miniature swine that are treated for 12 d with a high dose of cyclosporin A develop tolerance to MHC class II matched, class I-mismatched renal allografts. The aim of this study was to clarify the intrarenal allograft events associated with the development of tolerance in this protocol. Morphologic and immunologic studies were performed in serial biopsies from accepting grafts after 12 d of cyclosporin A treatment (n = 4) and were compared with those from untreated control rejecting grafts (n = 4). In accepting grafts with stable function, a transient interstitial infiltrate developed. The cellular infiltrate had many similarities to that in rejecting grafts; both had T cells and macrophages, similar proportions of T-cell subsets, and a similar frequency of in situ nick end labeling (TUNEL)+ apoptotic infiltrating cells. However, the cellular infiltrate in the acceptance reaction was distinguished by less T-cell activation (interleukin-2 receptor+), less proliferation (prolif...
Effect of Cyclosporin A on the in Situ Inflammatory Response of Human Renal Allograft Rejection
Scandinavian Journal of Immunology, 1982
of Cyciosporin A on the in Situ Infiammatory Response of Human AUograft Rejection. A Preliminary Report. Scand. J. Inmimol. 16, 135-149, 1982. Twenty cadaveric kidney aUograft recipients were prerandomized into two groups. Ten patients (control group) were treated postoperatively with azathioprine fAZA) plus methylprednisolone (MP): ihe other ten received cyciosporin A (CyA)as Ihc only imnnino^upprcssive agent. Both groups received MP during rejection. One patient was excluded from the CyA group because of an early postoperative cardiac infarction and death. All iransplants were monitored by alternate-day tine-needle aspiration biopsy and transplant aspiration cytology. Some patients treated wiih CyA had a significant initial decrease in urine output, reaching control values approximately I week postoperatively. Tlie mechanism liehind this deteriorated lenal function is not clear, but it seemed to have been caused by injuries to the kidney tubular component, since a distinct nionocytic-lymphocyiic inflammation and severe cytoiogical changes resembling pronounced acute tubular necrosis were observed concomitantly in transplant aspiration cytology. The CyA-treated patients had normal levels of hlood leucocytes, thrombocytes and lymphocytes but displayed a suong early blood cosinophilia that was absent in the control subjects. During the first . "^0 days after transplantation 15 in situ episodes of inflammation were recorded in the nine transplants treated with CyA, whereas only 6 episodes were found in the 10 transplants receiving AZA +MP(P-,-0.01). The first inflammatory episode in the ( yA-treated Iransplants (leaked between days 5 and 8 after transplantation and was followed by another distinct innammatory episode lietween days I'y and 26. In the AZA-plus MP-treated transplants, only one innammalion episode was observed, with a peak on day 14 posioperatively. The inflammatory cell types most prominently present in the CyA-treated transplants were lymphocytes, B plasniabJasts and monocyte;;. The early inflammatory episodes in the CyA-treated transplants may have been related to the fact that during the initial intramuscular administration, iherapeutie CyA concentrations in patient serum were not achieved until the fourth postoperative day during peroral administration. The onset of transplant function had no impact on the in situ inflammatory response of rejection in the CyA-treated transplants or on the concentration of CyA in patient serum. This indicates that CyA may also be used in initially nonfunctioning transplants, Confirming our earlier results, we were unable to demonstrate the major histocompatibility complex (MHC) antigens on the healthy grafts ireated with AZA plus MP. However, in healthy allografts treated with CyA, both classes of MHC antigens were^ nearly invariably demonstrable on the graft endothelial cell surface. Approximately 60% aUograft survivals were recorded in both groups al 6 months, and all patients with functioning grafts were able to work.
Induction of allograft tolerance through costimulatory blockade: first selection of drugs in vitro
Transplant Immunology, 2003
The development of an in vitro assay predicting the chances of graft survival after treatment with immunoregulatory agents is a major topic in transplantation. Antibodies (Abs) interfering in the costimulatory pathway are promising candidates for the induction of tolerance. To evaluate these antibodies for clinical use studies non-human primates are the only feasible option due to species specificity of the antibodies. Peripheral blood mononuclear cells, isolated from a large panel of rhesus monkeys, were used in a unidirectional mixed lymphocyte reaction to evaluate the ability of antibodies blocking the costimulatory pathway, to affect both primary and secondary proliferative and cytolytic allospecific immune responses in vitro. These blocking antibodies were also used in protocols prolonging allograft survival in a life-supporting kidney allotransplant model in rhesus macaques. The ultimate aim is to establish a correlation between parameters obtained in vitro and the success of transplantation in vivo. The combination of anti-CD80 and anti-CD86 resulted in a complete abrogation of the primary alloresponse as measured in a proliferation assay. Adding anti-CD40 significantly reduced this inhibitory effect although the in vivo effects of this antibody have been shown to be beneficial. The secondary response was most prominently inhibited by the combination of anti-CD80y86. Paradoxically, anti-CD40 alone markedly inhibited the secondary proliferative response, but did not add to the inhibitory effect of the combination of anti-CD80y86. The cytolytic response was inhibited maximally only when CsA was added to the combination of anti-CD80y86. Treatment with monoclonal antibodies alone without immunosuppressive drugs was sufficient to maintain graft survival during the time of treatment in most animals. However, rejection was initiated as soon as the treatment ceased and no tolerance, resulting in long-term graft and patient survival, was established. The complete inhibition of primary alloresponses and the partial inhibition of secondary proliferative alloresponses correlate with prolonged graft survival during treatment, but have no predictive value for the success of tolerance induction for kidney allografts in rhesus monkeys. ᮊ
The American Journal of Pathology, 2008
Acute humoral rejection (AHR), which occurs in up to 8% of kidney transplant recipients, is a significant cause of renal allograft dysfunction and loss. More efficacious treatment modalities are needed to eliminate or curtail alloantibody production and its deleterious effects on the kidney. The availability of animal models mimicking human AHR is essential to understand its pathophysiology and develop new treatment strategies. Using a mouse kidney transplant model, we demonstrate that presensitization of recipients with donor skin grafts results in rejection of subsequent renal allografts. All presensitized mice developed renal failure 8.6 ؎ 4.3 days after engraftment, with serum creatinine values near 100 mol/dl. Graft histology revealed mild, diffuse, interstitial, mononuclear cell infiltrates; prominent peritubular capillary inflammatory cell margination; patchy interstitial hemorrhage; interstitial edema; and focal glomerular fibrin deposition. Complement (C3d) deposition was diffuse and prominent in peritubular capillaries. Serum analysis demonstrated high levels of circulating alloantibodies with broad cross-reactivity to many MHC haplotypes. The clinical setting and histological findings of our model strongly resemble AHR, which is frequently associated with cellular rejection, a situation commonly encountered in human renal allograft recipients. This animal model provides a valuable tool to study the pathogenesis of AHR, its relationship to cellular alloimmunity, its contribution to graft injury, and the effects of various potential therapeutic interventions.
Transplant International, 2003
This study examined whether a heart or kidney graft could provide protection for the more resistant skin graft. Buffalo rat recipients were given a single dose of RIB 5/2 (non-depleting anti-CD4 mAb) plus i.v. Lewis splenocytes 21 days before being given Lewis heart or kidney grafts. Lewis skin was grafted either simultaneously with, or after, long-term (>50 days) Lewis heart or kidney allograft acceptance. Immune responsiveness was analyzed by in vitro mixed lymphocyte culture (MLC), cytotoxic T lymphocytes (CTLs), and limiting dilution analysis (LDA). While i.v. alloantigen plus RIB 5/2 resulted in long-term acceptance of heart and kidney, survival of skin grafts alone was not prolonged. However, simultaneous transplantation with kidney, but not heart, resulted in long-term skin graft acceptance, while skin grafts subsequently grafted to recipients tolerant to kidney or heart were not accepted. In vitro analysis revealed a down-regulation of proliferation, cytotoxicity, and precursor T-helper cells (pThs)/precursor cytotoxic T lymphocytes (pCTLs) in Buffalo recipients accepting Lewis kidney and skin allografts. While RIB 5/2 plus Lewis splenocytes do not prolong the survival of skin grafts, Lewis skin grafted simultaneously with a kidney, but not heart, is accepted indefinitely and provides donor-specific protection for a subsequent skin graft.
New Insights Into Mechanisms of Allograft Rejection
The American Journal of the Medical Sciences, 1997
Understanding of the molecular basis of organ allograft rejection has increased tremendously in the past decade. Insight into the nature of the alloantigen and the mechanisms underlying T cell recognition, activation, and differentiation provide novel targets for immunotherapy. Appreciation of the role that peptides present in the human leukocyte antigen groove play in allorecognition provides a new target for synthetic peptide therapy. Elucidation of signal transduction pathways downstream from the T-cell receptor helps to explain the mechanism of action of immunosuppressive agents and impacts the design of new drugs. An understanding of the role of costimulatory molecules, such as CD28, has given rise to new therapies, such as CTLA4-Ig. Information about the mechanisms of cytotoxicity, chemoattraction, and vascular biology similarly has provided new targets for rational drug design. This article highlights new insights into the mechanism of allograft rejection relevant to the design of new immunotherapies. KEY INDEXING TERMS: Transplantation; Allograft rejection; Immunology; Human leukocyte antigen (HLA); T lymphocytes. [Am J Med Sci 1997;313(5):257-263]. W hen an organ from one member of a species is transplanted into another, nonidentical, member of the species, there is an allogeneic (nonself) immune response directed at the foreign anti