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We report the case of a renal transplanted patient, in whom the detection of a unique anti HLA-DP antibody response preceded the development of chronic humoral rejection. In addition to donor-specific anti-DP alloantibodies, the patient displayed reactions against several non-donor-specific DP antigens (NDSA). Interestingly, we found that all the DP molecules recognized by the alloantibodies displayed the same amino-acid sequence suggesting that epitope sharing between unrelated HLA molecules was the mechanism underlying NDSA generation. This case highlights the pathogenicity of anti-DP alloantibodies and suggests that it could be more meaningful to match the epitopes than the HLA antigens for the prevention of rejection.

Several investigators have reported that hepatocyte growth factor (HGF) may be related to the protection or reconstruction of the kidney during acute renal rejection. To address this question, we examined the relationship between HGF and acute rejection in the following two studies with rat renal transplantation models. In study 1, the relationship between serum HGF levels and acute renal rejection in iso-, allo- and allograft with cyclosporine (CsA)-treated models was examined. In study 2, the focus was whether or not the injection of recombinant HGF can prevent acute renal rejection. Our results demonstrated that HGF levels were rapidly increased during acute rejection and that recombinant HGF effectively protected the kidney from acute rejection. These results suggest that HGF may be induced as a counter-response to the renal injury and that it can be used as a reliable indicator for the diagnosis of acute rejection. We suggest that recombinant HGF suppresses the onset of the pathological changes of acute rejection.

Background: Second-set rejection is generally regarded as a phenomenon mainly mediated by humoral cytotoxic antibodies, although a few discordant data have been presented. In the reported experiments, we have taken advantage of the absence of production of specific cytotoxic alloantibodies contrasting with the normal development of transplantation cellular immunity, in two murine models: chimeric mice and RAG mice., Methods: Chimeras (BALB/c-->CBA) were obtained by transplantation of 2x10(7) fetal liver cells from BALB/c (H-2d) mice to lethally irradiated CBA (H-2k) mice. After hyperimmunization with third-party C57/ BL6 (B6) (H-2b) skin transplants and with injections of 2x10(7) B6 spleen cells, antibody production, and skin graft survival were analyzed. To identify further the factors or cells responsible for accelerated rejection of B6 skin transplants in hyperimmunized chimeras, transfer experiments were carried out involving the injection of serum, whole spleen cells, spleen T cells, spleen CD8+ T cells or spleen CD4+ T cells from chimeras into BALB/c mice that had received 6 Gy irradiation. The recipient mice were then grafted with B6 skin. Similarly, the immunodeficient RAG mice were used to construct a model of recipient animals with anti-H-2d hyperimmunized B6 T cells in the total absence of antibody., Results: In chimeras, anti-B6 cytotoxic antibodies were not detectable in any of hyperimmunized chimeric mice, yet accelerated rejection of B6 skin transplant occurred: a graft survival of 8.6+/-0.5 days (d), comparable to 8.9+/-0.8 d survival in CBA control mice subjected to the same hyperimmunization procedure, and significantly shorter than that in nonhyperimmunized (BALB/c-->CBA) chimeras (11.6+/-0.5 d) or in non-hyperimmunized CBA control mice (12.1+/-0.6 d). High titers of anti-B6 cytotoxic antibodies were present in the serum of hyperimmunized CBA control mice. In transfer experiments, the graft survival was over 14 d in mice treated with irradiation alone, with irradiation + serum or with irradiation + CD4+ T cells. It was significantly shorter in mice treated with irradiation + whole spleen cells, with irradiation + T cells or with irradiation + CD8+ T cells (8.9+/-0.8 d). Similarly, in immunodeficient RAG mice, reconstitution of the T cell compartment with T cells from hyperimmunized B6 mice led to accelerated rejection of BALB/c skin allografts (11.4+/-1.1 d vs. 18.8+/-0.8 d when T cells were provided by nonimmunized mice). In a second transfer of cells from these reconstituted RAG mice into naive RAG mice, CD8+ T cells were shown to induce accelerated rejection of skin allografts (12.0+/-0.6 d) whereas CD4+ T cells were much less efficient (16.5+/-0.1 d)., Conclusion: These data indicate that T cells, and especially the CD8+ subset, can be responsible for second-set rejection in the absence of anti-donor antibodies in chimeric and RAG mouse models. These sensitized CD8+ T cells are also likely to play an important role in normal mice, in addition to that of cytotoxic antibodies.

IFN-gamma and IL-10 secretion by sorted T cell subsets of irreversibly rejected kidney graft-infiltrating cells (GIC) and normal PBMC was studied by ELISPOT. The low spontaneous frequency of IFN-gamma-producing cells (IFN-gamma-PC) was strongly increased by anti-CD3 activation within unsorted, CD3+CD4+, and CD3+CD4- subsets of GIC and PBMC. In contrast with PBMC, IL-10-PC from GIC were at higher frequency within CD4+ cells than among CD4- ones (P < 0.03). Four kidneys removed after 3.7 +/- 0.8 months showed acute vascular rejection, high frequency of activated CD4+ IL-10-PC (118 +/- 68 per 10(4) cells), and high percentage of anti-class II antibody reactivity (87.6 +/- 6.3%). In contrast, four patients with kidneys removed later (53.7 +/- 1.6 months, P = 0.02) displayed chronic rejection with superimposed acute cellular rejection, low frequency of CD4+ IL-10-PC (7.0 +/- 3.0 per 10(4) cells, P = 0.02), and low percentage of anti-class II antibody reactivity (12.9 +/- 6.1%, P = 0.02). Thus, accelerated vascular rejection appears to be associated with preferential production of IL-10 by activated CD4+ GIC, which may act by shifting the effector arms of alloreaction toward humoral responses.

The aim of this prospective and randomized study was to determine whether misoprostol, an analogue of PGE1, could decrease the incidence and the number of rejection episodes and could improve the renal function over a 12-month follow-up, when given at 400 micrograms/day for 12 months in renal transplant patients. Given the known side-effects and the additive cost of misoprostol, a benefit of the therapy should be a decrease of at least 50% in the incidence of rejection episodes in the treated group. Therefore, 60 consecutive renal transplant patients were randomized to receive misoprostol or to receive aluminium and magnesium hydroxide. Patients received steroids, azathioprine, antithymocyte globulins, and cyclosporin A (CsA). CsA was randomly started on day 0 or on day 8. At 12 months, no difference in the incidence of rejection episodes was observed: 63.3% in the 30 patients of the misoprostol + group versus 70.0% in the misoprostol-group (P = 0.558 Mantel-Cox). The renal function, assessed by plasma creatinine, inulin, and para-aminohippuric acid clearances, was not significantly different between misoprostol + and misoprostol-groups. No episode of CsA nephrotoxicity was observed in any patient of group one or group two. At 12 months, the mean dosage of CsA was 4.9 +/- 0.28 mg/kg/day in the misoprostol + group versus 4.52 +/- 0.23 mg/kg/day in the misoprostol-group and the trough level was not significantly different between the two groups. The graft survival rate at 12 months was 86.7% in the Misoprostol + group and 83.33% in the misoprostol-group.(ABSTRACT TRUNCATED AT 250 WORDS)

Second-set rejection is generally considered to be mediated by cytotoxic humoral antibodies. A few discordant data have been reported, however. To address this question, we have taken advantage of a model in which specific cytotoxic alloantibodies are not produced although transplantation cellular immunity develops. Following a transplant of allogeneic stem cells from fetal liver, chimeric mice (BALB/c-->CBA--i.e., H-2d-->H-2k) were obtained; virtually all peripheral blood lymphocytes and spleen cells were of BALB/c donor origin. Anti-sheep red blood cell humoral response was present, although significantly lower in chimeras than in controls. These allochimeras were hyperimmunized by skin grafts and injections of spleen cells. The survival of skin grafts and the production of antibodies were then analyzed. When hyperimmunized against a third party, B6 (H-2b), chimeric mice were not able to raise a detectable humoral response involving anti-B6 cytotoxic antibodies, yet they rejected B6 skin allografts in an accelerated fashion (8.44 +/- 0.17 days). Control CBA mice rejecting second-set B6 skin grafts within the same delay developed high-titer, specific cytotoxic antisera (mean titer = 140). These data show that cytotoxic allospecific antibodies are not indispensable in the development of second-set accelerated rejection of skin allografts.

The study aimed at analyzing the role of CMV infection as a risk factor for rejection occurring after CMV infection because of the clinical consequences of the prevention of CMV infection that might lead to the decrease in rejection episodes. Two hundred forty-two consecutive renal transplant patients were prospectively checked for the occurrence of CMV infection. CMV infection was defined virologically by a positive viremia or/and a positive viruria or/and a seroconversion or/and a significant rise of the anti-CMV antibody titers. Viremia, viruria, and serology were performed weekly for the first month and then at day 90, day 180, and every 6 months, and moreover if clinical symptoms related to a viral infection occurred. Rejection episode was defined by a creatininemia rise of 25%, after cyclosporine nephrotoxicity and urological complications had been discarded, and by the response to the antirejection therapy, steroids, or OKT3 in case of steroid-resistant rejection. The outcome factor was rejection episode occurring from day 4 after the diagnosis of CMV infection. A patient undergoing "a rejection episode after CMV infection" could also be exposed to other potential confounding factors that can be considered as risk factors of rejection among our patients. Rejection occurring before CMV infection was the main factor because it was linked both to CMV infection itself and to "rejection after." Thus infected and noninfected patients were randomly paired off. To the noninfected patient of the pair was attributed the date of a fictitious CMV infection that was the date of the CMV infection of the infected member of the pair. Therefore, "rejection after" and "rejection before" were defined in infected and noninfected patients of the pair according to the time of onset of CMV infection of the infected member of the pair. The incidence of CMV infection was 65%, 157 of the 242 patients were infected, and 85 not infected. Thus 85 pairs of infected-noninfected patients were studied. The incidence of "rejection after" the diagnosis of CMV infection was significantly higher in the group of patients with CMV infection: 45% among infected (38/85) versus 10.60% among noninfected (9/85) (P < 0.0001). Among the 85 pairs, 48 pairs were concordant in which patient of the pair evinced the same outcome factor: 43 showed no rejection after, and 5 showed one.(ABSTRACT TRUNCATED AT 400 WORDS)

The frequency of isolated low-density graft-infiltrating cells (GIC) secreting IFN-gamma, IL-6, and IL-10 was studied in 8 cases of irreversible rejection of human renal allografts, using ELISA and SPOT-forming cells (ELISPOT) assays. The GIC were mostly CD8+ T cells, although CD4+ T cells, B cells, and macrophages could also be detected. On the average, in 10(6) cells, 189 secreted IFN-gamma, 747 IL-10, and 17114 IL-6. Culture of GIC in the presence of IL-2 resulted in an increase in the frequency of IFN-gamma-producing cells (IFN-gamma-PC), in a dose-dependent manner, with an optimal 6.5-fold increase at 50 U/ml. In contrast, 25 U/ml IL-4 decreased the frequency of spontaneous and IL-2-induced IFN-gamma-PC by 71.3% and 52.8%, respectively. Furthermore, IL-4 reduced the frequency of IL-6-PC (56.8%). By this new approach to graft rejection, it becomes easier to determine cytokine profiles within an allograft and to study their modulation by different agents. It could be a useful model of study for the development of new treatment.

Using ELISPOT assays, we detected a significant number of cells secreting interferon-gamma and interleukin 6 among 8 irreversibly rejected kidney allografts compared with normal kidneys. Interleukin 2 increases the frequency of interferon-gamma producing cells and interleukin 4 decreases the frequency of both interferon-gamma and interleukin 6 producing cells.

The relative importance of renal biopsy and cytological studies (fine needle aspiration biopsy and urine sediment examination by phase contrast) in the diagnosis of acute rejection episode was evaluated in 30 patients who received a kidney transplant. All patients underwent these 3 examinations simultaneously during an acute degradation of graft function. Sensitivity of renal biopsy, fine needle biopsy and urine sediment was 0.86, 0.68, 0.43 respectively. The association of fine needle biopsy and urine sediment examination increased the sensitivity up to 0.73. Renal biopsy is indicated to assess the vascular and glomerular status or in the presence of inconclusive cytological studies.

Immunosuppressed patients are known to be susceptible to infectious agents. Association of allograft rejection and herpes virus infection (high incidence of cytomegalovirus) was yet reported after renal transplantation. Authors studied 19 rejection episodes on 24 renal transplantation performed for 17 months, cytomegalovirus infection being associated in 7. Because of the therapeutic difficulties observed in these cases, a preventive attitude is necessary.

In scintigraphic studies of renal transplants the absence of renal perfusion and clearance have been demonstrated to have many possible pathologic etiologies, vascular obstructions, and rejections. Increased perinephric activity was suggested as a sign of renal infarction and its absence may indicate potential renal viability. A case is presented in which a hyperactive halo was seen when the graft was dying.

The major histocompatibility complex (MHC) genes, coding for the histocompatibility leukocyte antigens (HLAs) are located on the short arm of chromosome 6. The HLA gene products are involved in many immune responses. Class I and class II molecules are composed of two subunits. Class I antigens are expressed on all cell types except red blood cells; class II molecules have a more limited distribution and are found only on certain cell types. A review of our current knowledge of the genes coding for these molecules, their biochemical analysis, and the current investigation into the three-dimensional structure of the glycoproteins will allow us to understand better how this complex system, which has been preserved in animal species throughout the evolutionary process, operates. The biologic significance of HLA class I and class II molecules in the development of an efficient immune system that permits our survival in the sea of microorganisms in which we are immersed is illustrated by the severe and lethal infections that occur when these antigens are absent. Important and interesting variations in class II antigen expression are also observed in certain autoimmune diseases. Furthermore, the role of these antigens in the allogeneic reaction of graft rejection has now been clearly identified. It has become increasingly apparent how important it is to understand the antigenic variation between organs, or even between cells within an organ, and to be able to identify the circumstances that are associated with modulation of antigen expression.