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Results for “rejection”

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PubMed1998

IL-2 and IL-4 double knockout mice reject islet allografts: a role for novel T cell growth factors in allograft rejection.

T cell growth factors (TCGFs) play a critical role in allograft rejection by promoting the activation and proliferation of alloreactive T cells. To determine whether IL-2 and IL-4 are of quintessential importance in allograft rejection and to identify possible alternative TCGFs, we have bred IL-2(-/-) and IL-4(-/-) double knockout (DKO) mice and studied islet allograft rejection using the DKO mice as allograft recipients. Although mononuclear leukocytes from DKO mice did not mount a proliferative response in vitro in response to anti-CD3 stimulation, crude islet allografts were vigorously rejected by DKO mice (mean survival time 17 +/- 7, n = 8) as compared with wild-type controls (mean survival time 13 +/- 4, n = 7). Treatment of DKO mice with anti-CD3 or rapamycin markedly prolonged the islet allograft survival. An analysis of intragraft cytokine gene transcripts showed robust expression of IL-7 and IL-15. In contrast, intragraft IL-9 gene transcripts were not detected in either wild-type or DKO mice. Provision of exogenous IL-2, IL-4, IL-7, or IL-15, but not IL-9, supports the proliferation of anti-CD3 activated DKO splenic leukocytes in vitro. Blocking the common gamma c of IL-2 receptor, a shared essential signaling component by receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, prolonged the survival of islet allografts in DKO mice. Hence, a T cell dependent allograft rejection enabled by rapamycin-sensitive signals or signals mediated by binding of the gamma c chain occurs in the absence of both IL-2 and IL-4. Non-T cell-derived TCGFs, especially IL-7 and IL-15, may play an active role in supporting allograft rejection.

Animals↗

PubMed1991

Mechanisms of rejection during OKT3 therapy: propagation and characterization of CD3 resistant allospecific cytotoxic T cells from a rejecting liver allograft.

Allograft rejection remains the single largest impediment to success in the field of transplantation. While OKT3 therapy has proven to be a significant advancement, many grafts are still lost. Late treatment, subtherapeutic OKT3 levels, anti-OKT3 antibodies, and OKT3-induced class II antigen expression are possible explanations. To determine the mechanism of OKT3 resistant rejection we propagated and characterized infiltrating T cells from the biopsy of a liver transplant patient who was rejecting while on prophylactic OKT3. The T lymphocytes demonstrated allospecific proliferation and interleukin 2 (IL2) production and showed a high degree of cytolysis of donor splenocytes. CD3 epsilon monoclonal antibodies (Mab) in concentrations up to 100 micrograms/ml did not inhibit lysis. In contrast, T lymphocytes derived from rejecting allografts of patients receiving cyclosporine and prednisone were readily inhibited from killing by CD3 epsilon Mab at doses of 1 microgram/ml. Furthermore, allospecific proliferation and IL2 production were not inhibited in the OKT3-treated patient by the addition of CD3 epsilon MaB. Incomplete modulation of the CD3-TCR complex was noted after a 72-hr incubation with CD3 epsilon Mab. The T cells did demonstrate other intact CD3-mediated functions such as a rise in intracellular calcium and CD3-dependent cytotoxicity. These results should alert clinicians that CD3 resistant cytotoxic T cells can emerge during OKT3 therapy and may cause rejection. Immunotherapy that targets additional cell surface structures may be of benefit.

Antibodies, Monoclonal↗

PubMed1994

Analysis of the inflammatory leucocyte mobilization in 838 fine needle aspiration biopsies in non-rejecting (day 1-90) kidney grafts and 465 biopsies in grafts before, during and after acute cellular rejection.

A total of 1303 fine needle aspiration biopsies (FNABs) were performed in all 105 kidney transplanted patients at our institution during 1990-1992: 838 were in patients who never had an acute cellular rejection (ACR), and 465 were in patients who had experienced an ACR; 393 of these FNABs were performed in first rejections and 72 in second rejections. The immunosuppressive protocol included monotherapy with cyclosporin A and an initial, additional course of Minnesota-ALG during the first ten days after transplantation (Tx). OKT3 was first-line antirejection therapy accompanied for a short period with prednisolone and azathioprine to oppose the development of anti-OKT3 antibodies. FNABs were taken each day for the first three days after Tx, then twice a week for the first month, and then at each visit to the outpatient clinic for the next three months. In non-rejecting grafts the total corrected increment (median) of the inflammatory response (TCI) increased from 1 to a maximum of 3.5, 17-21 days after Tx followed by a slight decrease. The inflammatory response was mainly due to non-activated lymphocytes. In the rejecting grafts the TCI (median) increased from three days before ACR to a maximum of 7 on the day of ACR, followed by a decrease when OKT3 treatment was started. The infiltrating cells were activated lymphocytes, other lymphocytes and, in smaller amounts, macrophages and monocytes.

Biopsy, Needle↗

PubMed1999

Does subclinical rejection contribute to chronic rejection in renal transplant patients?

Renal allograft biopsies have traditionally been performed in the setting of acute graft dysfunction. However, several groups have performed graft biopsies at times of stable graft function, and more recently, after treatment of rejection episodes. Surprisingly, unequivocal histologic criteria for acute rejection have been demonstrated in a high proportion of these protocol biopsies. The Winnipeg Transplant Group has documented the high prevalence of clinically silent inflammatory infiltrates in early protocol biopsies, and demonstrated their inflammatory and cytotoxic potential by immunohistochemical and molecular biological techniques. Furthermore, in a randomized trial, our group has demonstrated that subclinical rejection, if untreated, is associated with the development of early chronic pathology and late graft dysfunction. In this overview, we will summarize the early data on subclinical allograft inflammation, present the experience of the Winnipeg Transplant Group, and discuss the possible implications of subclinical rejection on the development of chronic rejection.

Biopsy↗

PubMed1981

Cells mediating graft rejection in the mouse. I. Lyt-1 cells mediate skin graft rejection.

The Ly phenotype of cells mediating skin graft rejection was determined using monoclonal anti-Lyt-1.1 and Lyt-2.1 antibodies in CBA mice that received CBA lymphoid cells from mice sensitized to C57BL/6; i.e., alloantigenic differences arising from the H-2 and non-H-2 loci. It was clear that graft rejection was due wholly to the presence of Lyt-1 cells in the inoculum and that Lyt-123 or Lyt-23 cells had no effect. Furthermore, no synergism was noted between Lyt-1 and Lyt-2 cells. In this model, both the cytotoxic T cell and cytotoxic lymphocyte precursors were shown to be Lyt-123 and these could be depleted from sensitized Lyt-1 populations that mediated graft rejection. Thus cytotoxic T cells are not responsible for skin graft rejection, but rather, this is mediated by an Lyt-1 cell. Whether this T cell is distinct from other Lyt-1 cells (T helper, T cells mediating delayed hypersensitivity) is not clear at present, but other evidence, and traditional concepts, link graft rejection and delayed type hypersensitivity as being different manifestations of the same mechanism.

Animals↗

PubMed1987

Liver allograft rejection. An analysis of the use of biopsy in determining outcome of rejection.

Two-hundred-seventy biopsy specimens from 47 patients undergoing liver transplants at the University of Minnesota were analyzed to determine if histological features could predict the eventual outcome of rejection episodes. Thirty-six patients (76.6%) rejected the transplant. Of these, five either suffered acute liver failure due to rejection (two cases) or developed chronic rejection (three cases). Features of significance in predicting such a bad outcome were arteritis, bile duct paucity, or simultaneous hepatocellular ballooning and hepatocellular dropout and necrosis. Other features, such as type and intensity of infiltrate, degree of bile duct damage, or simple presence of hepatocellular necrosis, were not predictive of outcome. Our conclusion is that biopsy is useful in predicting outcome. Since many of the histologic findings of predictive value were not present in initial pretreatment biopsy specimens, follow-up biopsies of patients being treated for rejection are recommended to assess efficacy of therapy.

Adolescent↗

PubMed1983

Immune mechanisms in organ allograft rejection. I. Delayed-type hypersensitivity and lymphocytotoxicity in heart graft rejection.

Sublethally irradiated (780 rads) rats receiving fully allogeneic heart transplants were reconstituted with sensitized lymphocytes fractionated into helper and cytotoxic/suppressor T cell subsets according to reactivity with monoclonal antibodies W3/25 and OX8, and the phenotype and functional activity of cells causing rejection was examined. Though the adoptive transfer of T cells of either subset in adequate numbers (0.5 X 10(6] was able to cause rejection, helper T cells were found to be significantly (P less than .02) more potent on a per-cell basis. The reconstituting inocula in this model system acted not simply to amplify a specific immune response by the irradiated host. Cytotoxic T cells appearing in sublethally irradiated heart graft recipients reconstituted with unfractionated T cells were shown to derive from the reconstituting inoculum. Cells with cytotoxic activity for donor-strain thymic blasts were undetectable in spleen or graft of recipients reconstituted with isolated T helper cells (OX8-), but were present in grafts of a high proportion of rats reconstituted with OX8+ cells. T cells within the helper subset (W3/25+ OX8-) were shown to be responsible for adoptive transfer of delayed-type hypersensitivity (DTH) and were phenotypically distinct from cytotoxic cells and their precursors (W3/25- OX8+). Heart graft rejection appears, therefore, to be mediated independently by lymphocyte subsets responsible exclusively for DTH or lymphocytotoxicity. Support for this observation was obtained by demonstrating prominent nonspecific recruitment of lymphocytes and monocytes in graft rejection, as well as frequent direct anatomic contact between infiltrating mononuclear cells and myofibers. This report provides, therefore, substantial evidence for a primary role for DTH in vascularized organ allograft rejection--but at the same time it indicates that cytotoxic T cells may play an independent pathogenic role.

Animals↗

PubMed1988

Effector mechanism in rejection of allografts expressing an isolated minor histocompatibility disparity. Importance of cytotoxic T lymphocytes in the rejection of H-43a allografts by H-43b mice.

To explore effector mechanisms in allograft rejection, we transplanted skin grafts (SG) across a single minor histocompatibility locus (H-43) using mouse strains carrying the H-43b allele as SG recipients and those carrying the H-43a allele as SG donors. Recipients' spleen cells (SC) were assayed at various intervals for 200 days for anti-H-43a cytotoxic T lymphocyte (CTL) responsiveness, as well as delayed-type hypersensitivity (DTH) responsiveness. When H-43a SG from C3H.SW mice were transplanted to H-43b CWB mice, two thirds of the recipients rejected the SG, and recipients' SC showed marked self-H-2Kb-restricted anti-H-43a CTL responsiveness until the end of the observation period. In contrast,H-43aSG transplanted to H-43b (B10.BRxCWB)F1 (BWF1) mice survived in almost all of the BWF1 recipients. The anti-H-43a CTL responsiveness of the recipients' SC was evident until day 40 but thereafter started to wane and eventually disappeared. Notably, BWF1 mice whose self-H-2Kb-restricted anti-H-43a CTL precursors had been primed by prior injection with H-43a SC rejected H-2Kb-bearing H-43a CSW SG but not H-2k, H-43a C3H/HeN SG. In contrast, an anti-H-43a DTH response was not induced in any of the CWB and BWF1 recipients, including CWB recipients who rejected the H-43a SG. Since it has been well documented that anti-H-43a CTL are restricted solely by self-H-2Kb, the results in this study indicate that self-H-2Kb-restricted anti-H-43a CTL are responsible for rejection of H-43a allografts by H-43b recipient mice.

Animals↗

PubMed1990

The role of tumor necrosis factor in allograft rejection. I. Evidence that elevated levels of tumor necrosis factor-alpha predict rejection following orthotopic liver transplantation.

Plasma levels of tumor necrosis factor-alpha were measured in 50 adult patients following orthotopic liver transplantation. The mean (+/- SEM) plasma concentration of TNF-alpha was significantly higher in patients experiencing a rejection episode (941 +/- 83 pg/ml) than in those with a stable clinical course (240 +/- 6 pg/ml; P = 0.0001). Peak levels of TNF-alpha were usually found at the time of clinically diagnosed rejection, although elevated levels were observed 1-2 days earlier. First-week peak TNF-alpha levels were significantly higher in patients who suffered graft loss (2146 +/- 788 pg/ml) than in those who were discharged from the hospital without clinical evidence of rejection (581 +/- 93 pg/ml; P = 0.004). TNF-alpha levels were not correlated with white blood cell count (r2 = 0.004), cyclosporine levels (0.01), serum creatinine (0.002), serum bilirubin (0.05), serum SGOT (0.03), or SGPT (0.05). TNF-alpha levels were not elevated in four cases of viral hepatitis occurring after transplantation. We conclude that circulating levels of TNF-alpha are elevated during liver allograft rejection and may precede clinical manifestations. First-week TNF-alpha levels are also useful predictors of long-term graft outcome. Further investigation is required to determine whether this monokine is important in the actual pathogenesis of allograft rejection.

Adolescent↗

PubMed1990

Platelet-activating factor and hyperacute rejection. The effect of a platelet-activating factor antagonist, SRI 63-441, on rejection of xenografts and allografts in sensitized hosts.

The pathogenesis of hyperacute transplantation reactions includes the activation of a cascade of nonspecific inflammatory reactions that precipitates the destruction of the target organ. Platelet-activating factor (PAF) represents an important component of these inflammatory cascades, and we have examined the influence of a specific PAF receptor antagonist (SRI 63-441) on the inhibition of hyperacute rejection in two experimental models, the rejection of rat cardiac allografts by presensitized recipients and guinea pig-to-rat and mouse-to-rat cardiac xenografts. Our results demonstrate that inhibition of PAF function by SRI 63-441 has a variable effect on the survival of cardiac allografts in presensitized rat recipients. In the ACI to sensitized BN cardiac allograft model, the use of SRI 63-441 alone, or in combination with CsA, FK506, or prostaglandin E2 (PGE2), does not prolong graft survival. As we have previously reported, SRI 63-441 does act as a single agent to prolong the survival of ACI to sensitized LEW grafts, and this survival effect is synergistic when combined with CsA. Here we extend these results to demonstrate that this survival is also extended when FK506 is used in the ACI-to-LEW model. Concordant mouse-to-rat cardiac xenografts are also relatively resistant to prolongation of graft survival following treatment with SRI 63-441 alone or in combination with CsA or FK506. Discordant xenografts appear to be more susceptible to inhibition of the rejection reaction with SRI 63-441. When either donor or recipient animals were treated with SRI 63-441 alone, or in combination with CsA or FK506, there was significant prolongation of guinea pig-to-rat cardiac xenograft survival. These results are consistent with our earlier description of the effectiveness of SRI 63-441 in preventing the rejection of cat-to-rabbit kidney xenografts. We believe that these results demonstrate that the use of the SRI 63-441 to specifically interfere with the function of PAF has the effect of prolonging graft survival in those systems in which performed antibody and/or complement activation are important components of the hyperacute reaction. This synthetic drug is representative of a family of compounds whose structure can be modified to balance their therapeutic and toxicity activities, and may prove to be important components of a polytherapeutic approach to the control of graft rejection in sensitized patients or following discordant xenografting.

Animals↗

PubMed1991

The role of tumor necrosis factor in allograft rejection. III. Evidence that anti-TNF antibody therapy prolongs allograft survival in rats with acute rejection.

We have previously demonstrated that TNF-alpha levels are elevated in liver transplant patients experiencing acute rejection. In addition, prophylactic administration of anti-TNF-alpha or anti-TNF-beta antibodies prolonged graft survival in a rat heterotopic cardiac transplant model. This experiment was designed to evaluate anti-TNF therapy in the treatment of acute allograft rejection. Heterotopic cardiac transplants were performed using Buffalo donors and Lewis recipients. Histologic sections of transplanted grafts from untreated animals revealed significant rejection at day 4 with terminal rejection occurring on day 10.8 +/- 0.4. Animals in the experimental groups received antirejection therapy from postoperative days 4-13. Treatment with cyclosporine at 2 mg/kg/day prolonged graft survival to 16.5 +/- 2.0 days (P = 0.01 versus controls). Administration of polyclonal anti-TNF-alpha in combination with polyclonal anti-TNF-beta increased graft survival to 14.6 +/- 0.4 days (P less than 0.001 versus controls). Use of a monoclonal anti-TNF-alpha antibody was even more effective, with graft survival of 17.4 +/- 0.7 days (P less than 0.001 versus controls). Combination immunotherapy with monoclonal anti-TNF-alpha in conjunction with CsA extended survival to greater than 30 days. In contrast, recombinant TNF-alpha (5 micrograms/day, i.p.) markedly accelerated the time to graft failure (7.4 +/- 0.2 days, P less than 0.001 versus controls). Examination of explanted graft tissue on postoperative day 9 from animals treated with anti-TNF showed decreased mononuclear cell infiltrate when compared to untreated animals. Treatment with TNF-alpha markedly increased the inflammatory process. These results suggest that TNF may play a role in the pathogenesis of acute rejection.

Animals↗

PubMed1992

Patterns of corneal graft rejection in the rabbit and reversal of rejection with monoclonal antibodies.

The purpose of this study was to determine whether the local administration of monoclonal antibodies could reverse rabbit corneal graft rejection. To provide a rational basis for the choice of monoclonal antibodies as potential immunosuppressive agents, the phenotypes of cells infiltrating rejecting rabbit corneal allografts were examined by immunohistochemistry. About half the leukocytes accumulating in these grafts bore an immunodominant T cell marker, over two-thirds carried MHC class II antigens, and about one-fifth carried myeloid cell markers. A kinetic study of the cell population appearing in rabbit aqueous during corneal graft rejection was performed by examination of repetitive anterior chamber taps taken over a ten-day period; again, the major components were T cells, MHC class II antigen-positive cells and myeloid cells. Monoclonal antibodies L11/135 (directed against a peripheral T cell determinant), 2C4 (directed against a monomorphic MHC class II antigen), and LION 2 (directed against a myeloid antigen) were chosen for intracameral injection into rabbits with rejecting corneal grafts. Each animal received a total of 50-100 micrograms of antibody in two injections at 3-4-day intervals. L11/135 and LION 2 reversed rejection in 5/9 and 8/12 animals, respectively, in the absence of any other immunosuppression; 2C4 was without effect. We suggest that monoclonal antibody therapy in corneal transplantation deserves further attention.

Animals↗

PubMed2002

The effect of acute rejection and cyclosporin A-treatment on induction of platelet-derived growth factor and its receptors during the development of chronic rat renal allograft rejection.

BACKGROUND: In the development of chronic kidney allograft rejection acute rejection (AR) is the single most important risk factor. Although Cyclosporin A (CsA) medication has decreased the incidence of AR, chronic rejection (CR) is still the major reason for late allograft loss. Platelet-derived growth factor (PDGF) is a major mitogen mediating mesenchymal cell proliferation in CR. We have investigated the impact of AR and different doses of CsA on the expression of PDGF ligands and receptors in the development of CR. METHODS: Kidney transplantations were performed from DA to WF rats and syngenic controls were done from DA to DA rats. Two groups of allografts were treated daily with CsA either at low dose (1.5 mg/kg) or high dose (5 mg/kg). Third group of allografts was treated with CsA 5 mg/kg/day for 1 week and then left untreated until the development of AR. AR episodes were treated with CsA 5 mg/kg/day. Grafts were harvested 3 months after transplantation for histology and immunohistochemistry (PDGF-AA, -BB and PDGFR-alpha, -beta). RESULTS: In syngenic grafts no histological signs of CR were seen and the expression of PDGF ligands and receptors remained almost nonexistent. AR episodes increased the chronic rejection changes. High-dose CsA-treatment ameliorated inflammation compared to low-dose CsA-treatment, although it failed to inhibit the development of chronic changes. More fibrosis was even seen in high-dose than in low-dose CsA-treated grafts. CR in each allograft group was associated with induction of all PDGF ligands and receptors (P<0.05 compared with syngenic controls) in interstitial inflammatory cells, capillary endothelium, and arterial smooth muscle cells. In the group with AR episodes the expression was further increased. CONCLUSIONS: Our results demonstrate that CsA treatment cannot inhibit the expression of PDGF ligands and receptors in the development of chronic kidney allograft rejection and that AR episodes induce even more PDGF and its receptors in the graft indicating a link between AR and subsequent development of CR.

Animals↗

PubMed1992

DNA associated with the cell membrane is involved in the inhibition of the skin rejection response induced by infusions of photodamaged alloreactive cells that mediate rejection of skin allograft.

Cell membrane DNA (cmDNA) is a form of DNA located on the surface of human and murine T-cells. It has recently been characterized as a target for photomodification by 8-methoxypsoralen (8-MOP) and long-wave ultraviolet light (UV-A). Whereas 8-MOP itself is biologically inert, photoactivated 8-MOP is covalently bound to pyrimidine bases in DNA. We have investigated the possible involvement of cmDNA photomodification in the induction of the suppression of skin allograft rejection in BALB/c mice preimmunized with 8-MOP/UV-A photodamaged alloreactive cells which mediates this allograft rejection. This suppression is demonstrated by inhibition of delayed-type hypersensitivity (DTH) and mixed leukocyte culture (MLC) responses. Splenocytes from BALB/c mice undergoing rejection of CBA/j skin graft which contained an expanded population of the effector T lymphocytes that mediate the rejection were treated with DNAse to remove cmDNA before or after treatment with 8-MOP and UV-A prior to infusion into naive BALB/c recipients. Mice that received pretreated effector cells were tested for MLC responses to CBA/j or B10 alloantigens before and after the DTH response. The DTH response of all groups of pretreated BALB/c mice to the relevant alloantigen was specifically suppressed as compared with the response of control mice. However, adoptive transfer of the suppression of the DTH response was optimally demonstrable only in syngeneic recipients of cells from donor mice treated with photodamaged alloreactive cells. Also, splenocytes from BALB/c mice immunized with photodamaged alloreactive cells demonstrated highly significant hyporesponsiveness and suppression of the MLC response of naive mice to the relevant alloantigen in the case of the primary MLC response, and to both alloantigens in the secondary MLC response which was totally eliminated by prior pretreatment of these effector cells with DNAse. Therefore, it appears that the suppression of the DTH response can be induced by pretreatment of the effector cells with DNAse and/or 8-MOP and UV-A but is adoptively transferable optimally only from mice which are recipients of photodamaged alloreactive cells. Moreover, the effectiveness of this treatment is decreased by prior removal of cmDNA from these cells. The presence of cmDNA is necessary for induction of suppression of the primary and secondary MLC responses in mice treated with photodamaged cells of allograft rejection.

Animals↗

PubMed1994

Characterization of mixed syngeneic-allogeneic and syngeneic-xenogeneic islet-graft rejections in mice. Evidence of functional impairment of the remaining syngeneic islets in xenograft rejections.

Allogeneic mouse islets or xenogeneic rat islets, or fetal porcine islets were implanted under the renal capsule of C57BL/6 mice either alone or carefully mixed with syngeneic islets. With this experimental model the syngeneic islets, although not rejected themselves, are exposed to cytokines and inflammatory mediators released during either allograft or xenograft rejection. No differences in insulin content could be observed between mixed islet grafts and pure syngeneic islet grafts 6 wk after transplantation. Neither was there any morphological evidence of a non-specific destruction of syngeneic islets. These findings suggest that the mechanisms of both allograft and xenograft rejections are highly specific. The hormone release from the mixed syngeneic-allogeneic grafts was similar to that from pure syngeneic islet grafts. In contrast, a pronounced impairment of both the first and second phases of insulin release was observed 2 wk after implantation in mixed syngeneic-xenogeneic islet grafts. When perfusing the mixed islet graft after completed rejection of the concordant xenogeneic rat islets (6 wk after implantation), the insulin release from the remaining syngeneic mouse islets was identical to that of control grafts. However, syngeneic mouse islets exposed to the rejection mechanism of the discordant xenogenic pig islet-like cell clusters did not attain a complete functional recovery.

Animals↗

PubMed2000

Subclinical rejection--a potential surrogate marker for chronic rejection--may be diagnosed by protocol biopsy or urine spectroscopy.

Our studies of protocol biopsy studies have shown that normal allograft histology can not be assumed by crude tests of renal function such as the serum creatinine concentration, and that there is a high prevalence of subclinical rejection in the first 6 months post-transplant (7, 13-17). The apparent ability of urine MR and IR spectra to reliably identify patients with normal allograft histology, if confirmed in a larger database, will preclude the need for a protocol biopsy in approximately 20-50% of patients. Conversely, finding urine MR or IR spectra characteristic of subclinical rejection would provide the opportunity for early treatment. The clear separation between patients with normal histology from those with subclinical rejection can be attributed to the use of the whole urine spectrum to develop the classifiers. Additional advantages of using MR or IR spectra of urine as a diagnostic tool compared to the biopsy include simplicity (i.e. no processing is required), low cost, rapid turnaround (i.e. < 15 minutes/sample), and, particularly, low risk, thus allowing for repetitive sampling. The ability to non-invasively diagnose acute inflammation in the kidney would be of great assistance in the post-transplant monitoring of renal transplant patients. Indeed, by following subclinical inflammation as detected in the MR/IR spectra it will be possible to tailor the intensity of the immunosuppression to the inflammatory status of the graft, thus minimising the risks of both insufficient and excessive immunosuppression. Furthermore, by following subclinical inflammation, as detected in the MR/IR spectra, it will be possible to test the hypothesis that subclinical rejection (i.e. persistence of its MR/IR spectral classifier) is a surrogate marker for the development of chronic rejection.

Acute Disease↗

PubMed1990

Graft rejection by cytolytic T cells. Specificity of the effector mechanism in the rejection of allogeneic marrow.

Cellular effector mechanisms of allograft rejection remain incompletely described. Characterizing the rejection of foreign-marrow allografts rather than solid-organ grafts has the advantage that the cellular composition of the marrow graft, as a single cell suspension, can be altered to include cellular components with differing antigen expression. Rejection of marrow grafts is sensitive to lethal doses of radiation in the mouse but resistant to sublethal levels of radiation. In an effort to identify cells mediating host resistance, lymphocytes were isolated and cloned from spleens of mice 7 days after sublethal TBI (650 cGy) and inoculation with allogeneic marrow. All clones isolated were cytolytic with specificity for MHC encoded gene products of the allogeneic marrow donor. When cloned cells were transferred in vivo into lethally irradiated (1025 cGy) recipients unable to reject allogeneic marrow, results utilizing splenic 125IUdR uptake indicated that these MHC-specific cytotoxic clones could suppress marrow proliferation. In order to characterize the effector mechanism and the ability of the clones to affect final engraftment, double donor chimeras were constructed so that 2 target cell populations differing at the MHC from each other and from the host were present in the same marrow allograft. Results directly demonstrated an ability of CTL of host MHC type to mediate graft rejection and characterized the effector mechanism as one with specificity for MHC gene products.

Animals↗

PubMed1989

A prospective comparison of murine monoclonal CD-3 (OKT3) antibody-based and equine antithymocyte globulin-based rejection prophylaxis in cardiac transplantation. Decreased rejection and less corticosteroid use with OKT3.

To test the efficacy of murine monoclonal CD-3 antibody (OKT3) in early prophylaxis for cardiac allograft rejection, we conducted a 6-month trial, prospectively assigning 51 patients to receive either equine antithymocyte globulin-based (n = 25) or OKT3-based (n = 26) early prophylaxis. ATG patients received 8 days of ATG (10 mg/kg), with the first dose given preoperatively. OKT3 patients received 14 days of OKT3 (5 mg) beginning on the second postoperative day. Corticosteroid and azathioprine administration were similar during early prophylaxis. Cyclosporine was begun preoperatively in ATG patients and on the fourth postoperative day in OKT3 patients. In addition, patients in both groups were randomized to receive or not receive eight weekly administrations of vincristine (0.025 mg/kg). While infection rate (0.8 +/- 0.2 infections/patient in both groups [mean +/- SEM]) and mortality (1 patient in each group) did not differ, OKT3-based early prophylaxis delayed the first rejection episode (76 +/- 11 days vs. 36 +/- 8 days, P = 0.005) and decreased the risk of rejection during the 6-month follow-up (P less than 0.001, product-limit analysis). Overall, the OKT3 group manifested 1.5 +/- 0.2 episodes of rejection/patient compared with 2.2 +/- 0.2 episodes/patient in the ATG group (P = 0.036). Despite similar 6-month cumulative cyclosporine and azathioprine dosages, six month average corticosteroid administration was less in the OKT3 group (12.2 +/- 1.5 mg prednisone equivalent/m2/day versus 19.3 +/- 2.1 mg prednisone equivalent/m2/day, P = 0.008), fewer OKT3 patients subsequently required additional cytolytic therapy for rejection (2 [8%] versus 12 [48%], P = 0.001), and more patients in the OKT3 group were successfully weaned off maintenance corticosteroids (22 [88%] versus 11 [46%], P = 0.002). We conclude that, relative to an equine ATG-based protocol, OKT3-based early prophylaxis results in less rejection, permitting less chronic corticosteroid administration.

Antibodies, Monoclonal↗