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PubMed1989

Rejection of cultured keratinocyte allografts in the rat. Clinical implications and a possible clue to the enigma of skin graft rejection.

We have made a detailed analysis of the fate of Langerhans cell-free cultured keratinocyte allografts in two rat strain combinations, DA-to-PVG and DA-to-LEW, and compared the results with the rejection of conventional skin allografts in these strain combinations. The cultured keratinocyte layers were grafted both to the body surface using a technique to prevent wound contraction, and to the renal subcapsular site. Histological examination of grafts was made on days 2, 7, 10, 14, and 28 after transplantation. Donor-specific anti-class I MHC monoclonal antibodies were used to verify the donor origin of the keratinocytes. We report that the keratinocyte allografts are acutely rejected but, in contrast to the conventional allografts, do not evoke alloantibody responses. Rejection of the keratinocytes at the renal subcapsular site was as rapid as that of conventional skin grafts. However, rejection of keratinocyte grafts on the body surface was delayed by a few days when compared with conventional skin grafts. Immunosuppression with cyclosporine prevented the rejection of DA keratinocyte layers placed at the renal subcapsular site of PVG rats, but rejection followed soon after cessation of cyclosporine therapy. These data suggest that rejection is a major constraint for the clinical application of cultured keratinocytes, and that autografts must be used if permanent cover is required. Moreover, the findings have interesting theoretical implications relating to the much greater vulnerability to rejection of skin grafts compared with organ grafts. Our current and previous data also suggest that class II positive dendritic cells are the major stimulus to alloantibody production after tissue transplantation.

Animals↗

PubMed1990

Recovery of a normal coronary vascular reserve after rejection therapy in acute human cardiac allograft rejection.

During acute rejection, coronary vascular reserve is severely impaired in human orthotopic heart transplants. To evaluate the effects of rejection therapy on coronary vascular reserve, the ratio of peak-to-resting coronary flow velocity was assessed with a coronary Doppler catheter and a maximally vasodilating dose of intracoronary papaverine (12 mg) in nine allograft recipients without rejection (group 1) and in six recipients before and after treatment of an acute episode of rejection (group 2). All the patients had normal epicardial coronary arteries and were free of left ventricular hypertrophy. In group 2 during rejection, the coronary vascular reserve was significantly lower than in group 1, in which all the patients had a peak-to-resting coronary flow velocity ratio greater than 4 (2.3 +/- 0.5 vs. 5.4 +/- 0.8, respectively, p less than 0.001). In group 2 after treatment of rejection, the peak-to-resting coronary flow velocity ratio was similar to that of group 1 (4.7 +/- 0.8). Heart rate, left ventricular volumes and pressures, hemoglobin concentration, and arterial oxygen pressure were similar in the two groups. This study provides evidence that alterations of coronary vascular reserve because of acute rejection were reversible after treatment of the rejection episode.

Angiography↗

PubMed1992

Pancreas rejection. Significance of histopathologic findings with implications for classification of rejection.

To determine the significance of various histopathologic features of pancreatic rejection, we reviewed the pathology of 53 biopsies taken to rule out rejection [32 bladder drained, (BD); 18 non-BD]. Twenty-six biopsies from 23 patients with allografts which ultimately failed (FLD) (7 BD, 16 non-BD) were compared with 27 biopsies from 27 patients with allografts which continue to function (FXN) (25 BD, 2 non-BD). The groups are similar in regard to age, sex, and time after transplant to biopsy. The mean follow-up is 13 months for FLD grafts versus 35 months for FXN grafts (p < 0.0001). In BD grafts, decreases in urine amylase usually led to biopsy, while in non-BD grafts, hyperglycemia usually prompted biopsy. More patients with ultimately FLD organs (17 of 26) presented with elevated blood glucose (BG) than patients with FXN grafts (2 of 27) (p < 0.0001). Multiple histologic features were examined related to the acinar tissue, pancreatic ducts, islets, vessels, and nerves. Features which strongly correlated with a negative outcome included moderate to severe inflammation of acinar tissue (p < 0.0001), acinar tissue loss and fibrosis (p < 0.0087) and vascular luminal narrowing due to chronic rejection (p < 0.003). Twenty-one pancreases showed chronic rejection and were treated with OKT3 or anti-lymphocytic globulin (ALG), six of these continue to function 1.6-9 years after biopsy, including two who presented with elevated BG levels. A normal biopsy was found in nine pancreases, all of which continue to function. Vasculitis was only seen in biopsies with moderate to severe inflammation, whereas endothelialitis was also seen in association with mild inflammation, suggesting that vasculitis is a more aggressive lesion. A rejection classification is proposed with endothelialitis partly defining mild rejection and vasculitis defining severe rejection. We conclude that several biopsy features and elevation of BG are strongly correlated with a high probability of failure; however, antirejection therapy is justified because recovery of function occurs in some cases. A normal biopsy obviates the need for therapy and predicts a good outcome, as do mild histological findings of rejection.

Adolescent↗

PubMed1989

Humoral immunity in allograft rejection. The role of cytotoxic alloantibody in hyperacute rejection and enhancement of rat cardiac allografts.

The role of humoral immunity in graft rejection in the rat model remains controversial. Passive transfer of cytotoxic alloantibody (CAA) has resulted either in hyperacute rejection or in graft enhancement. This study examines the effect of transfer of CAA on cardiac allograft survival in three rat strain combinations that are fully mismatched at the major histocompatibility (MHC) loci. Strain-specific immune responsiveness in donor-recipient pairs varied from low (Lewis-to-ACI) to high (ACI-to-Lewis) as measured by mixed lymphocyte reactions. CAA was obtained from rats sensitized by three successive skin grafts at weekly intervals. Group 1 (high responder recipients), which consisted of Lewis rats presensitized to ACI and had a lymphocytotoxicity titer of 1:512 to 1:2048, rejected ACI cardiac allografts in 10.8 +/- 7.2 hr compared with 6.5 +/- 0.5 days in naive controls (p less than 0.001). Injection of 1 ml of high-titer CAA into naive Lewis rats immediately after ACI cardiac grafting led to hyperacute rejection of ACI hears in 2.1 +/- 0.8 hr while 1 ml of CAA followed by 2 ml of guinea pig complement (GPC) resulted in even faster rejection (mean survival time (MST) of 23.8 +/- 4.7 min). Injection of 2 ml GPC alone or in combination with 1 ml naive Lewis serum had no effect on graft survival. Multiple pretransplant injections of 1 ml of CAA on days -3, -2,-1, and 0 relative to transplantation resulted in significant prolongation of allograft survival (MST of 10.3 +/- 0.3 days; P less than 0.01). In group 2 (intermediate responder recipients), where Lewis rats were presensitized to WF strain and where cytotoxicity titer was 1:16 to 1:256, the recipients rejected WF hearts in 23.8 +/- 5.8 hr compared with 6.8 +/- 0.8 days in unsensitized control recipients (P less than 0.001). Injection of 1 ml of Lewis anti-WF CAA resulted in prolonged graft survival of 9.7 +/- 3.5 days, while injection of 1 ml of CAA followed by 2 ml of GPC caused hyperacute rejection in 104 +/- 61.7 min. Pretransplant injections of CAA on days -3, -2, -1, and 0 resulted in enhancement, with an MST of 16.3 +/- 1.3 days (P less than 0.001). In group 3 (low responder recipients), ACI presensitized to Lewis developed a cytotoxicity titer of 1:2 to 1:32 and rejected Lewis hearts in 5.3 +/- 0.4 days compared with 10.6 +/- 1.0 days in naive recipients.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1997

Cardiac allograft rejection: do trough cyclosporine levels correlate with the grade of histologic rejection?

BACKGROUND: The introduction of cyclosporine to heart transplantation immunosuppressive protocols has been associated with an improvement in the long- and short-term survival rates. The ideal dose of cyclosporine that maximizes its immunosuppressive properties and minimizes its toxicity has remained an enigma since its introduction. This study was undertaken to evaluate which range of cyclosporine levels provided the most effective protection against graft rejection. METHODS: We studied the correlation between cyclosporine levels and histologic grade of rejection, cardiac function, and renal function by retrospectively analyzing the results of 1407 individual whole blood cyclosporine trough levels. One hundred seven heart transplant recipients were studied within 2 years of undergoing transplantation. As a historical comparison, we also studied 146 individual trough cyclosporine levels from a subgroup of patients (n = 14) who had acute cellular rejection with graft dysfunction or failure. We correlated trough cyclosporine levels with the histologic severity of cellular rejection, cardiac function (right cardiac catheterization), and serum creatinine in both groups. The correlation was performed within patient's own data rather than between patient groups to avoid interpatient variations. RESULTS: The mean cyclosporine level was significantly higher (206 ng/ml) when the patients had grade 0 cellular rejection in comparison to grade 3A, with a mean cyclosporine level of 173 ng/ml (p = 0.005). Patients with graft dysfunction or failure had higher mean cyclosporine level (230 ng/ml) when they had no rejection compared with 3A rejection with a mean cyclosporine level of 153 ng/ml (p = 0.001). Furthermore, lower cyclosporine levels were associated with graft dysfunction. There was no correlation between serum creatinine and cyclosporine levels (r = 0.059, r2 = 0.351%). CONCLUSION: We conclude that cyclosporine trough levels above 200 ng/ml in the first 2 years after heart transplantation are associated with reduced cellular rejection without deleterious effects on renal function.

Adult↗

PubMed2001

Mycophenolate mofetil for the treatment of a first acute renal allograft rejection: three-year follow-up. The Mycophenolate Mofetil Acute Renal Rejection Study Group.

BACKGROUND: Mycophenolate mofetil (MMF) has previously been shown to be significantly better than azathioprine (AZA) in the treatment of first acute renal transplant (Tx) rejection by 6 months after initiation of treatment. This report analyzes the 3-year safety and efficacy data from this cohort of patients. METHODS: Renal Tx recipients with a first rejection episode occurring within 6 months after a first or second cadaver or living donor Tx were randomized, double-blind, to receive MMF (1.5 g b.i.d., n=113) or AZA (1-2 mg/kg, n = 108); both treatment arms also received i.v. corticosteroids (5 mg/kg/day for 5 days) followed by a steroid taper in conjunction with cyclosporine. Patients remained on blinded study medication for 1 year, after which they were converted to open-label study medication at the same dosage. All patients, including those who terminated early (<3 yr) were followed for patient and graft survival, chronic renal allograft dysfunction (CRAD), and malignancy. CRAD was determined by the presence of at least two of the following: a biopsy with chronic rejection, proteinuria >750 mg/day, or an increase in serum creatinine >1 mg/dl over baseline. Patients who continued to receive the assigned medication were followed for additional rejections, renal function, and adverse events including infections. RESULTS: A total of 67 (59.3%) MMF-treated and 56 (51.9%) AZA-treated patients completed the 3-year study; follow-up was available for all randomized patients except one. At 3 years, the cumulative incidence of first subsequent biopsy-proven or presumptive rejection while receiving study drug was 42.2% in the MMF-treated and 68.8% in the AZA-treated patients; a difference of 26.6% (95% confidence interval: 13.4-39.9%). At 3 years, 19.6% of all MMF-treated and 24.1% of all AZA-treated patients lost their Tx or had died. Renal function was similar in both groups. The combined end point of CRAD or Tx loss without CRAD occurred in 23% and 26% of all MMF- and all AZA-treated patients, respectively. Leukopenia, diarrhea, and abdominal pain were the most commonly associated adverse events of MMF treatment. Malignancies (predominantly cutaneous) occurred in 14.2% of MMF-treated patients and 10.2% of AZA-treated patients. Three lymphomas occurred in each treatment arm. CONCLUSION: The addition of MMF at the time of renal Tx rejection reduces the frequency of subsequent rejections without causing new limiting side effects. Although Tx survival was better in the MMF group, comparison with AZA was confounded by the rate of premature terminations in both treatment groups.

Adrenal Cortex Hormones↗

PubMedDate not supplied

The electrophysiology of cardiac allograft rejection: independent effects of rejection and perioperative ischemia on the sinus node recovery phenomenon after cardiac transplantation.

We characterized the effect of cardiac allograft rejection on the sinus node (SN) recovery response from overdrive suppression. A total of 54 corresponding data sets (SN recovery time [SNRT]/endomyocardial biopsy [EMB]) was available in 24 transplant recipients with normal SNRT. Data were pooled in the rejection vs the no-rejection group (n = 16 vs n = 38, respectively). During cardiac rejection (defined as a 7-day period starting 3 days prior to and lasting until 3 days after the EMB) the SNRT curves were moderately, but significantly shifted towards higher values (F = 13.4, p = .0003). All changes occurred within accepted normal limits for the SNRT. Multivariate analysis indicated independent effects of donor heart ischemic time (p = .0005) on SNRT in addition to that of rejection. After accounting for that influence of ischemic time respective F values regarding the influence of rejection on the SNRT excursions were 10.8 (ischemic time < 100 min, p = .0014) and 4.36 (ischemic time > or = 100 min, p = .039). This study shows that cardiac allograft rejection significantly delays the SN recovery response from overdrive suppression. These changes, however, are subtle and, hence, are an unlikely explanation for the often grossly abnormal postoperative SN function.

Adolescent↗

PubMed1998

Aggressive treatment of the first acute rejection episode using first-line anti-lymphocytic preparation reduces further acute rejection episodes after human kidney transplantation.

The detrimental effect of acute rejection episodes on long-term outcome of renal allografts in cyclosporin-treated patients is well established, although has not been seen by all investigators. To analyse the possibility that aggressive treatment of the first episode may ameliorate this detrimental effect, we performed an open label, randomised prospective trial in cyclosporin-based, immunosuppressed recipients of postmortem renal allografts in order to compare two different treatment protocols during primary acute rejection episodes: (1) group 1 of 25 patients received 3 x 250 mg methylprednisolone (MP) i.v.; (2) group 2 of 25 patients received 7 x anti-thymocyte globulin (ATG)-Fresenius i.v. (4 mg/kg body weight). During a period of 4 years, the following clinical observations were made: (1) The incidence of an acute re-rejection episode was significantly reduced in the ATG-treated study group (16%) compared to the MP-treated study group (72%); (2) The severity of the first acute rejection episode (intensity of renal dysfunction measured in terms of 10-day creatinine area under curve) showed no significant difference between the groups (37 mg x 10-d/dl to 58 mg x 10-d/dl); and (3) The half-lives of allografts in both groups have not shown any significant differences so far. In conclusion, aggressive treatment of the first rejection episode of renal allografts with the use of ATG reduced the incidence of re-rejection episodes which, however, are not reflected so far by improvement of the 4-year survival rate of these allografts. Since it could be observed that re-rejection is an even worse predictor for chronic transplant failure, a better long-term outcome of renal allografts in ATG-treated patients may be expected during a longer observation period. The incidence of a third episode was also reduced in the ATG-treated group (0%) compared to the MP-treated group (12%).

Adult↗

PubMed2005

Does perceived parental rejection make adolescents sad and mad? The association of perceived parental rejection with adolescent depression and aggression.

PURPOSE: To research the association of perceived parental rejection to adolescent depression and aggression. METHODS: This study focused on 1329 Dutch junior high and high school students (47.9% males and 52.1% females; age range 10-19 years) that completed depression, aggression and perceived parental rejection questionnaires. The data were analyzed by structural equation modeling that assumed a relationship between perceived parental rejection and adolescent aggression, as mediated by adolescent depression. RESULTS: Perceived parental rejection, mediated through adolescent depression, explains aggressive behaviors of adolescents, as tested by a mediation model. Additionally, the fit of this mediation model is somewhat enhanced when direct paths from perceived parental rejection to aggression are included. Further analysis demonstrates that these effects are also somewhat dependent on the gender and the age of the adolescents, as would be expected in light of previous studies of these cohorts. CONCLUSIONS: The study of perceived parental rejection should receive the same attention in the research of the development of both adolescent depression and aggression, as has been the case for adolescent peer rejection.

Adolescent↗

PubMed2003

Intragraft cytokine mRNA expression in rejecting and non-rejecting vascularized xenografts.

BACKGROUND: The aim of the present study was to further investigate the characteristics of both graft-infiltrating cells and splenocytes during acute vascular rejection (AVR), cell-mediated rejection and non-rejection of vascularized concordant xenografts, by analysing both proinflammatory [interleukin-1beta (IL-1beta) and tumour necrosis factor (TNF-alpha)] and more specific [(IL-2, IL-4, IL-10, IL-12p40 and interferon-gamma (IFN-gamma)] cytokines. A parallel investigation was made of the antibody response of IgM and IgG to the xenografts. METHODS: Mouse hearts were heterotopically transplanted to the neck vessels of recipient rats. Grafts, spleens and sera were collected from untreated (AVR) and cyclosporin A (CyA) treated animals on day 2 after transplantation. Organs from rats treated with 15-deoxyspergualin (DSG) or CyA and DSG in combination were harvested on both day 2 and day 8. Grafts from DSG-treated rats undergo cell-mediated rejection and stop beating on day 9 and forth, while CyA + DSG treatment results in long-term graft survival. Real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was applied for analysis of intragraft and splenic cytokine messenger RNA (mRNA) expression. The phenotypes of the graft infiltrating cells were characterized by immunohistochemistry. The antibody response was investigated by means of immunofluorescence, haemagglutination and flow cytometry. RESULTS: All the studied cytokines (IL-1beta, IL-2, IL-4, IL-10, IL-12p40, IFN-gamma and TNF-alpha) were up-regulated in the grafts from rejecting untreated (day 2) and DSG-treated animals (day 8) in comparison with grafts from CyA + DSG treated animals (day 8). On day 2 under immunosuppression with CyA, DSG or CyA + DSG no or low cytokine mRNA levels were found. The mRNA levels of IL-2, IL-4 and IFN-gamma in the spleens were suppressed under both DSG- and CyA + DSG treatment on day 8. Immunofluorescence showed deposits of both IgM and IgG in grafts from untreated, CyA-treated (day 2) and DSG-treated (day 8) animals, while CyA + DSG treatment diminished these deposits on both day 2 and day 8. No circulating antibodies were identified in either group. CONCLUSION: We hereby conclude that both AVR on day 2 and cell-mediated rejection on day 8 (under DSG treatment) in a concordant cardiac mouse-to-rat xenotransplantation model are associated with an increase of proinflammatory cytokines, T helper 1 (Th1)-associated cytokines as well as IL-10, while immunosuppression with CyA + DSG diminishes the levels of all examined cytokines. Grafts undergoing AVR or cellular rejection are subjected to deposits of both IgM and IgG, although circulating donor specific antibodies are undetectable in serum.

Acute Disease↗

PubMed1982

Cells mediating graft rejection in the mouse. II. The Ly phenotypes of cells producing tumor allograft rejection.

The particular T cell subsets involved in the rejection of tumor allografts were examined in mice using two different approaches. In the first, EL4 lymphoma cells or B16 melanoma cells were given to ATXBM-CBA/H mice which had been reconstituted with either naive or sensitized T cells selectively depleted with either Ly-1 or Ly-2 monoclonal antibodies. In mice receiving nonsensitized T cells, Ly-123 cells and to a lesser extent Ly-1 cells were involved in the rejection of both tumors: Ly-23 cells played no role in this rejection. By contrast, in mice receiving sensitized cells, rejection was mediated by Ly-1 cells and not by Ly-123 or Ly-23 cells. In a second approach, sensitized cells were mixed with the tumor cells prior to injection into mice (the Winn neutralization assay). In this case, Ly-123 cells were the prime mediators of graft rejection. We conclude that both Ly-1 and Ly-123 cells can act as mediators of graft rejection. Ly-1-sensitized cells probably act as in a delayed-type hypersensitivity (DTH) response where few lymphocytes can lead to the rejection of many cells. In addition, Ly-123 cells can act as killer T cells but large numbers and the close apposition with the target cells are required. Our results also demonstrate a requirement for Ly-123 precursor cells in nonsensitized mice, probably acting as precursors for both types of effector cell.

Animals↗

PubMed1985

Lung allograft rejection in the rat. I. Accelerated rejection caused by graft lymphocytes.

To find out to what extent rejection of lungs differs from that of other organs, functional rejection of lung allografts was studied in five combinations of inbred rat strains. Rejection could be monitored accurately by perfusion scintigraphy, and equally well by chest roentgenography. The rejection of lung grafts was found to proceed remarkably fast, when compared with heart grafts, in combinations with strong RT1-incompatibilities. This accelerated rejection pattern could be converted into rejection at a normal pace by pretreatment of the donor with 10 Gy roentgen irradiation one day before transplantation. Donor pretreatment depleted the lung graft's bronchus-associated lymphoid tissue (BALT) of lymphocytes. When grafts were depleted of all other passenger cells as well--by retransplantation from a cyclosporine-treated intermediate host--they showed an even more reduced immunogenicity, probably because of the loss of donor-type dendritic cells. These results indicate that lymphocytes from the BALT of lung grafts are capable of accelerating the rejection response.

Animals↗

PubMed1993

Reversal of ongoing heart, kidney, and pancreas allograft rejection and suppression of accelerated heart allograft rejection in the rat by rapamycin.

Rapamycin was examined for its effects on reversal of ongoing rejection of heart, kidney, and pancreas allografts and on suppression of accelerated heart allograft rejection in the rat. A 14-day continuous intravenous infusion of RAPA by an osmotic pump at 0.02, 0.08, and 0.8 mg/kg/day to WFu recipients, starting 4 days postoperation, significantly protected the BUF heart allografts with a mean survival time (MST) +/- 1 SD of 33.2 +/- 19.8 (p < 0.001), 48.2 +/- 14.8 (p < 0.001), and 107.0 +/- 86.3 (p < 0.001) days, respectively, as compared with 7.2 +/- 0.8 days in vehicle-treated controls. Combination of low dose RAPA (0.02 mg/kg or 0.08 mg/kg) and low dose CsA (2 mg/kg) achieved significantly longer cardiac allograft survival than RAPA or CsA alone. RAPA's effect in reversing ongoing rejection of renal and pancreatic allografts was also significant. The BUF kidney and pancreas in WFu recipients treated with a 14-day course of RAPA (0.8 mg/kg/day starting 4 days postoperation) had an MST of 44.7 +/- 15.9 (p < 0.001) and 46.4 +/- 12.5 (p < 0.001), while in vehicle-treated controls, the grafts were rejected within 10 days. RAPA could also suppress accelerated cardiac allograft rejection. Hyperimmunized WFu recipients were treated with two 14-day courses of continuous i.v. RAPA at 0.8 mg/kg/day before and after BUF heart allografting. Significantly longer survival of the grafts (25.5 +/- 3.7 days, p < 0.001) was achieved compared with that of the vehicle-treated controls (3.8 +/- 1.0 days). One-course RAPA treatment before or after heart transplantation was considerably less effective. RAPA was also shown to prevent the increase of serum IgG levels and to inhibit the production of specific cytotoxic Ab in the rat receiving repetitive immunizations. Such effects presumably contribute to the inhibition of the accelerated rejection. The results of this study suggest that RAPA is potentially useful in treatment of ongoing as well as accelerated allograft rejection.

Animals↗

PubMed1996

Prevention of chronic rejection by donor-specific blood transfusion in a new model of chronic cardiac allograft rejection.

Chronic graft rejection is now a major barrier to the long-term survival of cardiac transplants. A major hallmark of chronic rejection is intimal thickening of arteries in the graft leading to vascular occlusion. Current animal models of chronic rejection generally utilize immunosuppression to prevent acute rejection of grafts disparate at major histocompatibility antigens or graft disparities involving minor histocompatibility antigens alone. In the present communication we describe a new model of chronic rejection involving grafting of PVG-R23 hearts into PVG-RT1(u) recipients. The R23 hearts, which differ from the RT1(u) recipients at class II MHC, are rejected with a chronic time course and demonstrate extensive severe vascular myointimal proliferation within the coronary arteries. Furthermore we demonstrate for the first time that donor-specific blood transfusion can prevent chronic rejection and the intimal thickening of the coronary arteries.

Animals↗

PubMed1997

Expansion of intermediate T cell receptor cells expressing interleukin-2 receptor alpha- beta+, CD8alpha+ beta+, and lymphocyte function-associated antigen-1+ in the liver in association with intrahepatic islet xenograft rejection from rat to mouse: prevention of rejection with anti-interleukin-2 receptor beta monoclonal antibody treatment.

BACKGROUND: The precise mechanisms involved in islet xenograft rejection remain unknown. The purpose of the present study was to determine cellular mechanisms responsible for islet xenograft rejection in the liver to facilitate finding a procedure for prevention of immune rejection. METHODS: Hepatic mononuclear cells (MNC) as well as splenocytes, peripheral blood MNC, and thymocytes from streptozotocin-induced diabetic mice (BALB/c) rejecting the intrahepatic rat (Lewis) islet xenografts were isolated and examined by two-color FACS analysis. RESULTS: The characteristic finding of the hepatic MNC from the mice rejecting islet xenografts compared with mice receiving isografts was a significant increase in the yield as well as in the percentage of the cells expressing CD3+ interleukin-2 receptor (IL-2R) alpha- beta+, CD3+ CD8alpha+ beta+, and T cell receptor (TCR) alphabeta+ lymphocyte function-associated antigen-1+. The expression of CD3 and TCR alphabeta of these T cells was found to be of intermediate intensity (TCR(int) cells). The expansion of these TCR(int) cells occurred predominantly in the liver. There was no significant difference in the cells expressing CD3+ IL-2R alpha+, CD3+ CD4+, CD3+ TCRgammadelta+, CD3- IL-2Rbeta+ (natural killer cells), and B220+ (B cells). In vivo administration of anti-IL-2Rbeta monoclonal antibody directed to the expanded cells produced a prevention of rejection. CONCLUSIONS: These findings suggest that islet xenograft rejection in the liver from rat to mouse is an event for which the TCR(int) cells are responsible.

Animals↗

PubMed2005

IL-4 deficiency prevents eosinophilic rejection and uncovers a role for neutrophils in the rejection of MHC class II disparate skin grafts.

BACKGROUND: Acute rejection of MHC class II-disparate bm12 skin grafts by C57BL/6 recipient mice is characterized by massive graft infiltration by eosinophils, together with increased intragraft amounts of IL-4 and IL-5 mRNA. IL-5 blockade prevents the intragraft eosinophil infiltration and prolongs the survival of skin allografts. As the differentiation of T cell precursors into Th2 cells is largely driven by IL-4, we investigated the role of IL-4 in MHC class II-disparate allograft rejection. METHODS: We performed skin grafts from MHC class II incompatible bm12 mice into wild-type C57BL/6 mice (IL-4) or C57BL/6 IL-4 deficient mice (IL-4). Graft survival, in vitro T cell reactivity, and histology were compared. RESULTS: We observed that 50% of IL-4 mice rapidly rejected their bm12 allograft, whereas the other 50% retained their graft 60 days after transplantation. Histological examination of bm12 allografts retained by IL-4 mice showed a normal appearance with no inflammatory infiltrate and no eosinophils. Among IL-4 mice that acutely rejected their bm12 skin graft, we observed a dense polymorphonuclear infiltrate. The depletion of neutrophils significantly prolonged bm12 graft survival. CONCLUSIONS: Eosinophil infiltrates, typical of MHC class II disparate acute skin graft rejection, are critically dependent on the availability of IL-4. IL-4 mice reject MHC class II disparate skin grafts by a pathway of rejection where neutrophils play a direct causal role.

Animals↗

PubMed2004

Role of autoimmunity in organ allograft rejection: a focus on immunity to type V collagen in the pathogenesis of lung transplant rejection.

Lung transplantation is the only definitive treatment modality for many forms of end-stage lung disease. However, the lung is rejected more often than any other type of solid organ allograft due to chronic rejection known as bronchiolitis obliterans (BO). Indeed, BO is the primary reason why the 5- and 7-yr survival rates are worse for the lung than for any other transplanted organ. Alloimmunity to donor antigens is established as the primary mechanism that mediates rejection responses. However, newer immunosuppressive regimens designed to abrogate alloimmune activation have not improved survival. Therefore, these data suggest that other antigens, unrelated to donor transplantation antigens, are involved in rejection. Utilizing human and rodent studies of lung transplantation, our laboratory has documented that a native collagen, type V collagen [col(V)], is a target of the rejection response. Col(V) is highly conserved; therefore, these data indicate that transplant rejection involves both alloimmune and autoimmune responses. The role of col(V) in lung transplant rejection is described in this review article. In addition, the potential role of regulatory T cells that are crucial to modulating autoimmunity and alloimmunity is also discussed.

Animals↗

PubMed1989

A novel cell type responsible for marrow graft rejection in mice. T cells with NK phenotype cause acute rejection of marrow grafts.

Acute rejection of allogeneic and semiallogeneic marrow grafts has long been considered to be a function of the natural immune system because it shares many features with NK activity in mice. With the use of a recently developed in vivo adoptive transfer assay in which spleen cells are transferred from mice able to reject a particular marrow graft into mice that fail to do so, we show that the cells responsible for induction of marrow graft rejection indeed display the phenotype of NK cells: they lack the T cell Ag CD4 and CD8 but express the NK Ag NK1 and ASGM1. The rejection induced by adoptively transferred cells is exquisitely specific--a feature that points to a specific recognition process by the transferred cells. To elucidate what the recognition structure on these cells may be we found that they express CD3 and most likely the beta-chain of the TCR. Highly purified responder cells with the NK1+, CD3+, CD4-, CD8- phenotype, when transferred into nonresponder recipients, cause specific marrow graft rejection. We conclude that the acute rejection of bone marrow grafts is caused by a cell that expresses NK phenotype but is of T cell lineage. This may suggest the specificity of acute marrow graft rejection is caused by a specific recognition process that involves TCR.

Animals↗