Immunological Monitoring and Early Prediction of Rejection in Renal Allograft Recipients (original) (raw)
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Early Immunological Prediction of Renal Allograft Rejection
International Archives of Allergy and Immunology, 1987
Reliable predictors of impending renal allograft rejection would be valuable for better patient management. To date, no available test has been shown to be consistently predictive and results have often been conflicting. We evaluated an effector of cell-mediated immunity, antibody-dependent cell-mediated cyto toxicity (ADCC) as well as the response of these cells to different biological response modifiers (BRM) in pa tients following renal allograft transplantation. The in vitro test used assayed monocytes as ADCC effector cells against antibody-sensitized chicken red blood cells. The effects of BRM were studied by preincubating the monocytes with lymphoblastoid IFN, recombinant c^-interferon or y-interferon. A follow-up study was per formed on 47 patients with end-stage renal disease treated with renal allograft transplantation. ADCC activity and its response to BRM were assayed prior to transplantation, 2, 4, and 9 weeks post transplantation. In the case of rejection, ADCC was then studied prior to initiation of antirejection therapy and for 2 months follow ing treatment of rejection episode. We noted that in patients with stable grafts, the ADCC activity as well as its response to BRM declined gradually during the first 2 weeks post grafting and remained decreased up to 3 months after transplantation. In contrast, in recipients who experienced rejection episodes there was a sus tained and significant increase in ADCC response to BRM during the first 3 weeks post grafting. By the time the diagnosis of rejection had been established the baseline ADCC activity had also increased. Following treat ment and stabilization of the graft, ADCC activity and its response to BRM was decreased, similar to that in patients with stable grafts. Thus, by monitoring ADCC and the effect of different BRM on this activity we could predict rejection episodes in renal allograft recipients as early as 15 days in advance of any clinical or bi ochemical sign of rejection.
Transplantation
A significant percentage of biopsies from stable, well-functioning renal allografts have histologic findings consistent with acute rejection or borderline rejection. The implication of this finding is not yet fully understood. We analyzed immune-activation gene transcripts in stable protocol biopsies to determine the extent of immunologic activity of graft-infiltrating cells in this setting. Histologic classification of the biopsies was based on the Banff criteria. To emphasize that the tissue samples were procured from grafts with no clinical evidence of impaired function, we interjected the term "subclinical" into the Banff terminology. This produced three histologic categories: normal, borderline subclinical rejection, and acute subclinical rejection. We used competitive template polymerase chain reaction techniques to quantify transcript amounts for the constant region of the T-cell receptor beta chain; the cytokines, tumor necrosis factor alpha, interleukin (IL)-1beta...
Transplantation, 1998
A significant percentage of biopsies from stable, well-functioning renal allografts have histologic findings consistent with acute rejection or borderline rejection. The implication of this finding is not yet fully understood. We analyzed immune-activation gene transcripts in stable protocol biopsies to determine the extent of immunologic activity of graft-infiltrating cells in this setting. Histologic classification of the biopsies was based on the Banff criteria. To emphasize that the tissue samples were procured from grafts with no clinical evidence of impaired function, we interjected the term "subclinical" into the Banff terminology. This produced three histologic categories: normal, borderline subclinical rejection, and acute subclinical rejection. We used competitive template polymerase chain reaction techniques to quantify transcript amounts for the constant region of the T-cell receptor beta chain; the cytokines, tumor necrosis factor alpha, interleukin (IL)-1beta, transforming growth factor beta, interferon gamma, IL-2, IL-4, IL-10, and IL-15; and the cytotoxic T lymphocyte effector molecules, granzyme B, perforin, and Fas ligand. We found that histologically normal biopsies were typically devoid of gene transcripts or had very low amounts. Conversely, biopsies with acute subclinical rejection by histologic examination had heightened amounts of transcripts for many of the genes assayed. Borderline subclinical rejection samples showed an intermediate amount of expression. These results demonstrate that histologic features of rejection are often accompanied by enhanced expression of pro-inflammatory gene transcripts, despite the absence of clinically overt graft dysfunction. As this state of subclinical rejection could prove detrimental to long-term graft function, a role for surveillance biopsies of stable grafts with intent to treat subclinical rejection should be considered.
Clinical Transplantation, 2006
Abstract: A better understanding of the immunobiological processes and predictors of graft rejection holds promise for the development of potential therapeutic strategies and also individualization of immunosuppression. The objective of this study is to analyze the clinical relevance of immune parameters such as antidonor antihuman leukocyte antigen (anti-HLA) antibodies, monitoring of cytokines and their receptors on the graft outcome following live-related donor renal transplantation. Flow cytometry-based methods were used to detect antidonor antibodies (flow cytometry crossmatch, FCXM) and intracellular cytokines. Enzyme-linked immunosorbent assay (ELISA) methods were employed to detect anti-HLA class I and class II antibodies and quantitative serum-soluble interleukin-2 receptor (sIL-2R) levels. The data revealed that patients with HLA class I-specific IgG antibody experienced higher acute rejection (AR) episodes at 1 yr in comparison to the antibody negative group (82% vs. 56%, p = 0.01). On the contrary, donor-specific class II antibodies (B+) did not have any influence on the graft survival. However, 15 recipients having both T- and B-cell antidonor antibodies (T+B+) had significantly poor graft survival (60%) as compared to the antibody-negative group (T−B−, 82%, p = 0.05). Additionally, patients having non-donor but HLA-specific antibodies (FCXM−/ELISA+) had poor graft survival as compared to the antibody-negative group (64% vs. 88%, p < 0.05). Further, patients undergoing AR episodes had significantly higher expression of IFN-γ-producing T cells (19.16 ± 7.4% median 17.50) as compared to their pre-transplant levels (5.68 ± 1.63%, Median 5.20) and the non-rejecter group (5.97 ± 4.39%, median 4.3, p = 0.0004). Similarly sIL-2 was significantly increased in AR episodes during the first month of transplantation (292 ± 131.5 pmol/L) as compared to those with well-functioning grafts (p = 0.01) and healthy controls (p = 0.001). Evaluation of antidonor antibodies by flow cytometry is found to be relatively more sensitive and a better predictor of graft outcome. Further monitoring of cytokine expression profile of primed peripheral T-helper cells and quantitative analysis of sIL-2R offer additional valuable diagnostic and prognostic tools for follow-up of transplant subjects and a better alternative for functional assessment of immunosuppression.
Intragraft events preceding chronic renal allograft rejection in a modified tolerance protocol
Kidney International, 2000
renchymal cells and chronic rejection. Certain of the described Intragraft events preceding chronic renal allograft rejection in immunopathologic findings (activation, proliferation, apoptoa modified tolerance protocol. sis, and antibody deposition) may be useful in distinguishing Background. Inbred miniature swine treated for 12 days the type of rejection, that is, whether the allograft will progress with high-dose cyclosporine A develop tolerance to histocomto chronic rejection or recovery. patibility complex (MHC) class I-mismatched renal allografts. When this protocol was modified by adding thymectomy before transplant, all animals developed acute rejection. Thereafter, by day 100, one half developed chronic rejection (progression Inbred miniature swine are the only large animal in group) and the other half recovered (recovery group). This which one can reproducibly study the effects of selective provides an excellent experimental model to identify the mechanisms of chronic rejection as well as the early changes that matching within the major histocompatibility complex may predict chronic rejection. (MHC) on parameters of transplantation [1, 2]. They Methods. We assessed the cellular infiltration, immune actialso share many immunologic and physiologic properties vation, humoral immunity, and cell-and antibody-mediated with humans and are useful for preclinical studies [2, 3]. graft injury in the progression and the recovery groups. In Our group demonstrated that inbred miniature swine addition, we also examined circulating donor reactive cytotoxic T lymphocyte (CTL) and antidonor antibody in both groups. treated with 12 days of high-dose cyclosporine A (CsA) Results. From days 8 to 18 after transplantation, the two develop tolerance to MHC class II-matched, class I-misgroups were indistinguishable. Both showed acute rejection matched renal allografts [2, 4]. The thymus is necessary with endarteritis (type II); had IgG and IgM deposition in for rapid and stable tolerance induction in this model, glomeruli and small vessels; had an infiltrate with similar numpresumably caused by central selection mechanisms bers of T cells, proliferating (PCNAϩ) and activated (interleukin-2 receptorϩ) cells; and had a similar degree of parenchymal [5, 6]. If the protocol is modified by adding thymectomy cell apoptosis [in situ DNA nick-end labeling (TUNEL)ϩ]. 21 to 42 days prior to transplantation, only peripheral However, by days 30 to 60, the two groups could be distinmechanisms of tolerance can operate. The thymectomy guished by several intragraft features. The recovery group bemodel may be relevant to the usual adult human with came tolerant and had diminished T-cell infiltration, activation and proliferation, and no detectable antibody deposition. The an atrophic thymus. These thymectomized pigs develop number of TUNELϩ-injured parenchymal cells decreased. In prolonged graft dysfunction with acute rejection on days contrast, the progression group showed persistent cell infiltra-8 to 18 [5, 6]. In 50% of animals, chronic rejection with tion with activation and proliferation. Significantly prominent graft dysfunction develops by day 100. In the remaining TUNELϩ apoptotic parenchymal cells in tubules, glomeruli, 50%, dysfunction improves gradually with the developperitubular capillaries and arteries were seen from day 30 to day 100. Circulating donor reactive CTL and antidonor class ment of transplant tolerance, presumably by more effec-I IgG were detected in the progression group at higher levels tive peripheral mechanisms. than in the recovery group from days 30 to 60. Chronic rejection is one of the leading and intractable Conclusion. In tolerance-induction protocols, unstable tolcauses of renal allograft loss. Despite its devastating imerance induction is associated with the persistent immunologic pact on graft survival, the pathogenesis of chronic rejecactivation that mediates immunologic destruction of graft pation is still unclear and is believed to be multifactorial, including immunologic and nonimmunologic factors
Clinical and experimental nephrology, 2017
Ability to predict the manner in which a recipient's immune system would respond to a transplanted graft by analyzing cytokine profiles of the "allograft antigen sensitized" recipient lymphocytes in vitro might provide a means to identify patients at risk to adverse clinical endpoints. Cytokine/chemokine gene expression profiles of peripheral blood mononuclear cells co-cultured with allograft antigen-pulsed macrophages were studied in 49 renal transplant recipients-12 with acute cellular rejection (ACR) with or without antibody-mediated rejection (AMR), 7 with AMR (without ACR), and 30 with stable allografts (SA). An 86-gene inflammatory cytokines and receptors PCR array was used to measure fold changes in gene expression between pulsed and un-pulsed cultures. On linear discriminant analysis and multivariate analysis of variance, a gene set comprising C3, CCL3, IL1B, TOLLIP, IL10, CXCL5, ABCF1, CCR3, IL10RB, CXCL1, and IL1R1 differentiated the ACR-AMR from the SA group...
Through the Looking Glass: Unraveling the Stage-Shift of Acute Rejection in Renal Allografts
Journal of Clinical Medicine, 2022
Sub-optimal sensitivity and specificity in current allograft monitoring methodologies underscore the need for more accurate and reflexive immunosurveillance to uncover the flux in alloimmunity between allograft health and the onset and progression of rejection. QSant—a urine based multi-analyte diagnostic test—was developed to profile renal transplant health and prognosticate injury, risk of evolution, and resolution of acute rejection. Q-Score—the composite score, across measurements of DNA, protein and metabolic biomarkers in the QSant assay—enables this risk prognostication. The domain of immune quiescence—below a Q-Score threshold of 32—is well established, based on published AUC of 98% for QSant. However, the trajectory of rejection is variable, given that causality is multi-factorial. Injury and subtypes of rejection are captured by the progression of Q-Score. This publication explores the clinical utility of QSant across the alloimmunity gradient of 32–100 for the early diagn...
Transplantation proceedings, 2009
To study cellular alloimmunity in kidney allograft recipients using an interferon-gamma enzyme-linked immunosorbent spot assay (ELISPOT). Donor splenocyte peripheral blood mononuclear cells were obtained during kidney recovery in 53 kidney recipients including 11 with positive panel-reactive antibodies pretransplantation. For ELISPOT data analysis, the spot number, size, and intensity were calculated, reflecting the volume of cytokine secretion at the single-cell level. Results were recalculated as the ratio of the values observed for donor-stimulated to unstimulated recipient cells corrected for residual donor activity. Significantly greater pretransplantation donor-stimulated activity was observed in recipients who experienced an acute rejection episode (ARE) within 1 year (P < .05). Mean change in spot number, size, and intensity in patients without or with AREs was 0.99 vs 3.33, 1.60 vs 6.05, and 1.40 vs 6.31, respectively. The assessed parameters were prognostic of high risk...
Molecular Profiling of Acute and Chronic Rejections of Renal Allografts
Clinical and Developmental Immunology, 2013
Both antibody mediated (AMR) and T-cell mediated (TCMR) rejections either acute or chronic represent the main reason for late graft dysfunction. In this study we aimed to evaluate differences in the intrarenal expression patterns of immune system related genes in acute and chronic rejections. Graft biopsies were performed and evaluated according to Banff classification. Using the TaqMan Low Density Array, the intrarenal expressions of 376 genes relating to immune response (B-cell activation, T-cell activation, chemokines, growth factors, immune regulators, and apoptosis) were analyzed in the four rejection categories: chronic AMR, chronic TCMR, acute AMR, and acute TCMR. The set of genes significantly upregulated in acute TCMR as compared to acute AMR was identified, while no difference in gene expressions between chronic rejections groups was found. In comparison with functioning grafts, grafts that failed within the next 24 months after the chronic rejection morphological confirmation presented at biopsy already established severe graft injury (low eGFR, higher proteinuria), longer followup, higher expression of CDC20, CXCL6, DIABLO, GABRP, KIAA0101, ME2, MMP7, NFATC4, and TGFB3 mRNA, and lower expression of CCL19 and TRADD mRNA. In conclusion, both Banff 2007 chronic rejection categories did not differ in intrarenal expression of 376 selected genes associated with immune response.