Primary therapy with OKT3 for biopsy-proven acute renal allograft rejection

Our patient underwent right anteromesial temporal resection at 17 years of age for intractable complex partial seizures due to hippocampal sclerosis, and then developed juvenile myoclonic epilepsy after a change in medication. Postoperative seizures ceased after a change to valproate monotherapy. Our patient reminds us to remain aware that generalized and focal epilepsy may coexist as an unusual cause for surgical failure. We feel that these patients may still be favorable candidates for epileptic surgery, as long as the focal epileptogenic zone is amenable to resection and the generalized epilepsy appears to be readily controllable.     

The intragraft CD8+ T cell response in renal allograft rejection in the mouse

To identify the role of donor class I alloantigens in regulating the CD8+ T cell response to a kidney allograft, we analyzed and compared the CD8+ infiltrate in kidney transplants from MHC class I-deficient (class I-) mouse donors and class I+ controls. One week after transplantation, there was a prominent CD8+ infiltrate in control allografts, whereas CD8+ T cells were virtually absent in grafts from class I- donors. In class I+ allografts, infiltrating CD8+ cells utilized a wide range of T cell receptor (TCR) Vbeta families and their Vbeta usage was similar to that of the systemic CD8+ population. However, there was a modest but significant overrepresentation of cells bearing Vbeta8 in the graft compared with the spleen due to an expansion of CD8+ Vbeta8.3+ cells. This could be detected as early as 1 week and became more pronounced by 3 weeks after transplantation. In 3-week allografts, only 52% of CD8+ cells expressed alphabetaTCR. Among T cells isolated from class I+ grafts, the CD8+ Vbeta8+ cells demonstrated allospecific responses that were numerically larger than responses of the CD8+ Vbeta8- population. In contrast to the early (1 week) time point, significant numbers of CD8+ cells could be isolated from class I- grafts by 3 weeks after transplantation and their Vbeta repertoire resembled that seen in controls. While increasing numbers of CD8+ Vbeta8+ were present in the class I- grafts at 3 weeks, this increase was not statistically significant. Thus, expression of class I alloantigens on a kidney graft plays an important role in regulating the rate of accumulation of CD8+ T cells in rejecting kidney grafts. However, the TCR Vbeta repertoire of the CD8+ T cell infiltrate is largely determined by factors that are independent of normal class I expression on the graft.     

Successful induction and consolidation therapy of acute myeloid leukaemia in a renal allograft recipient

Immunosuppressed organ transplant recipients have a markedly increased risk of neoplasia. Among these malignancies acute myeloid leukaemia (AML) is rare. However, until now no case of successful chemotherapy has been reported. We present a 39-year-old male patient who developed AML (FAB M4 Eo) 4 years after renal transplantation and achieved a stable complete remission after induction therapy with standard dose cytarabine and daunorubicin. Remission duration is now 11 months. At present the transplant is functioning well after two additional courses of consolidation chemotherapy with high-dose cytarabine combined with mitoxantrone and idarubicine respectively. Cyclosporin A was given during all cycles of chemotherapy. We conclude that intensive chemotherapy in patients with AML following renal transplantation in good performance status is feasible.     

Macrophage migration inhibitory factor expression in human renal allograft rejection

BACKGROUND: Macrophage migration inhibitory factor (MIF) plays a pivotal role in immune-mediated diseases. Despite the long-standing association of MIF with the delayed-type hypersensitivity response, the potential role of MIF in allograft rejection is unknown. METHODS: MIF expression was assessed by in situ hybridization and immunohistochemistry staining in 62 biopsies of human renal allograft rejection and in normal human kidney. RESULTS: MIF mRNA and protein is constitutively expressed in normal kidney, being largely restricted to tubular epithelial cells, some glomerular epithelial cells, and vascular smooth muscle cells. In both acute and chronic renal allograft rejection, there was marked up-regulation of MIF mRNA and protein expression by intrinsic kidney cells such as tubular epithelial cells and vascular endothelial and smooth muscle cells. There was also MIF expression by infiltrating macrophages and T cells. Of note, macrophage and T cell infiltrates were largely restricted to areas with marked up-regulation of MIF expression, potentially contributing to the development of severe tubulitis and intimal or transmural arteritis. Quantitative analysis found that increased MIF expression in allograft rejection gave a highly significant correlation with macrophage and T cell accumulation in both the glomerulus and interstitium (P<0.001). In addition, the number of MIF+ tubules and interstitial MIF+ cells correlated significantly with the severity of allograft rejection (P<0.01), and the loss of renal function (P<0.01). In contrast, no up-regulation of renal MIF expression and no leukocyte accumulation was seen in allograft biopsies without evidence of rejection. CONCLUSIONS: This is the first study to demonstrate that local MIF expression is up-regulated during allograft rejection. The association between up-regulation of MIF expression, macrophage and T cell infiltration and the severity of renal allograft rejection suggests that MIF may be an important mediator in the process of allograft rejection.     

Delayed function reduces renal allograft survival independent of acute rejection

BACKGROUND: Mechanisms by which delayed allograft function reduces renal allograft survival are poorly understood. This study evaluated the relationship of delayed allograft function to acute rejection and long-term survival of cadaveric allografts. METHODS: 338 recipients of cadaveric allografts were followed until death, resumption of dialysis, retransplantation, loss to follow-up, or the study's end, which ever came first. Delayed allograft function was defined by dialysis during the first week following transplantation. Multivariate Cox proportional hazards survival analysis was used to assess the relationship of delayed allograft function to rejection and allograft survival. RESULTS: Delayed allograft function, recipient age, preformed reactive antibody levels, prior kidney transplantation, recipient race, rejection during the first 30 days and rejection subsequent to 30 days following transplantation were predictive of allograft survival in multivariate survival models. Delayed allograft function was associated with shorter allograft survival after adjustment for acute rejection and other covariates (relative rate of failure [RR]+1.72 [95% CI, 1.07, 2.76]). The adjusted RR of allograft failure associated with any rejection during the first 30 days was 1.99 (1.23, 3.21), and for rejection subsequent to the first 30 days was 3.53 (2.9 08, 6.00). The impact of delayed allograft function did not change substantially (RR=1.84 [1.15, 2.95]) in models not controlling for acute rejection. These results were stable among several subgroups of patients and using alternative definitions of allograft survival and delayed allograft function. CONCLUSIONS: This study demonstrates that delayed allograft function and acute allograft rejection have important independent and deleterious effects on cadaveric allograft survival. These results suggest that the effect of delayed allograft function is mediated, in part, through mechanisms not involving acute clinical rejection.     

Progressive albuminuria and glomerulosclerosis in a rat model of chronic renal allograft rejection

A significant proportion of renal allografts fail within several months or years after transplantation, primarily because of chronic rejection. The etiology and pathophysiology of this condition remain unclear. We studied the renal function, morphology, and immunohistology, in parallel, among F344-to-Lewis allografts (n = 23) and isografts (n = 13) over the course of 24 weeks. Only an initial 10-day course of CsA (5 mg/kg/day) was given to both groups to prevent acute rejection. Hypertension did not develop, although awake systolic blood pressure was significantly higher in allografts at the end of the study. Significant differences in urine albumin excretion (UalbV) between isografts and allografts were evident as early as 4 weeks after engraftment but rose dramatically by 20 weeks (3.3 +/- 0.7 vs. 21.2 +/- 3.7 mg/day, respectively, P < .001). This pattern continued until the conclusion of the study (5.0 +/- 1.1 vs. 53.5 +/- 7.6 mg/day, P < .001). Serum creatinine values were only significantly elevated in allografts at 16 weeks, which temporally corresponded to the dramatic increase in UalbV. However, renal blood flow and glomerular filtration rate, measured by paraaminohippurate and inulin clearances, respectively, were significantly lower in allografted organs, at 24 weeks. The frequency of glomerulosclerosis lesions was significantly increased in allografted kidneys at 24 weeks and correlated with UalbV values. Glomerular localization of mononuclear leukocyte subsets were equivalent between allografts and isografts; however, the numbers of interstitial macrophages, CD8+, and pan-T-cells were all significantly greater in allografts at 24 weeks. The infiltration of significantly greater numbers of macrophages and lymphocytes into the tubulointerstitium of the allograft group suggests a mononuclear leukocyte effector cell mediation of the progressive glomerular abnormalities in this model of chronic renal allograft rejection in the rat.     

Cyclosporine trough concentrations in predicting allograft rejection and renal toxicity up to 12 months after renal transplantation

We recently identified a novel gene (PB39) (HGMW-approved symbol POV1) whose expression is up-regulated in human prostate cancer using tissue microdissection-based differential display analysis. In the present study we report the full-length sequencing of PB39 cDNA, genomic localization of the PB39 gene, and genomic sequence of the mouse homologue. The full-length human cDNA is 2317 nucleotides in length and contains an open reading frame of 559 amino acids which does not show homology with any reported human genes. The N-terminus contains charged amino acids and a helical loop pattern suggestive of an srp leader sequence for a secreted protein. Fluorescence in situ hybridization using PB39 cDNA as probe mapped the gene to chromosome 11p11.1-p11.2. Comparison of PB39 cDNA sequence with murine sequence available in the public database identified a region of previously sequenced mouse genomic DNA showing 67% amino acid sequence homology with human PB39. Based on alignment and comparison to the human cDNA the mouse genomic sequence suggests there are at least 14 exons in the mouse gene spread over approximately 100 kb of genomic sequence. Further analysis of PB39 expression in human tissues shows the presence of a unique splice variant mRNA that appears to be primarily associated with fetal tissues and tumors. Interestingly, the unique splice variant appears in prostatic intraepithelial neoplasia, a microscopic precursor lesion of prostate cancer. The current data support the hypothesis that PB39 plays a role in the development of human prostate cancer and will be useful in the analysis of the gene product in further human and murine studies.