[show abstract][hide abstract] ABSTRACT: One of the leading causes of long-term kidney graft loss is chronic allograft injury (CAI), a pathological process triggered by alloantigen-dependent and alloantigen-independent factors. Alloantigen-independent factors, such as cold ischemia (CI) may amplify the recipient immune response against the graft. We investigated the impact of prolonged cold ischemia and the subsequent delayed graft function on CAI in a fully MHC-mismatched rat model of kidney allotransplantation. Prolonged CI was associated with anticipation of proteinuria onset and graft function deterioration (ischemia: 90d; no ischemia: 150d), more severe tubular atrophy, interstitial fibrosis, and glomerulosclerosis, and increased mortality rate (180d survival, ischemia: 0%; no ischemia: 67%). In ischemic allografts, T and B cells were detected very early and were organized in inflammatory clusters. Higher expression of BAFF-R and TACI within the ischemic allografts indicates that B cells are mature and activated. As a consequence of B cell activity, anti-donor antibodies, glomerular C4d and IgG deposition, important features of chronic humoral rejection, appeared earlier in ischemic than in non-ischemic allograft recipients. Thus, prolonged CI time plays a main role in CAI development by triggering acceleration of cellular and humoral reactions of chronic rejection. Limiting CI time should be considered as a main target in kidney transplantation.
Transplant International 03/2012; 25(3):347-56. · 3.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: Anemia can contribute to chronic allograft injury by limiting oxygen delivery to tissues, particularly in the tubulointerstitium. To determine mechanisms by which erythropoietin (EPO) prevents chronic allograft injury we utilized a rat model of full MHC-mismatched kidney transplantation (Wistar Furth donor and Lewis recipients) with removal of the native kidneys. EPO treatment entirely corrected post-transplant anemia. Control rats developed progressive proteinuria and graft dysfunction, tubulointerstitial damage, inflammatory cell infiltration, and glomerulosclerosis, all prevented by EPO. Normalization of post-transplant hemoglobin levels by blood transfusions, however, had no impact on chronic allograft injury, indicating that EPO-mediated graft protection went beyond the correction of anemia. Compared to syngeneic grafts, control allografts had loss of peritubular capillaries, higher tubular apoptosis, tubular and glomerular oxidative injury, and reduced expression of podocyte nephrin; all prevented by EPO treatment. The effects of EPO were associated with preservation of intragraft expression of angiogenic factors, upregulation of the anti-apoptotic factor p-Akt in tubuli, and increased expression of Bcl-2. Inhibition of p-Akt by Wortmannin partially antagonized the effect of EPO on allograft injury and tubular apoptosis, and prevented EPO-induced Bcl-2 upregulation. Thus non-erythropoietic derivatives of EPO may be useful to prevent chronic renal allograft injury.
Kidney International 02/2012; 81(9):903-18. · 7.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background. Ischemia/reperfusion (I/R) injury is an important cause of renal graft dysfunction. Increases in cold and warm ischemia times lead to a higher risk of early posttransplant complications including delayed graft function and acute rejection. Moreover, prolonged cold ischemia is a predictor of long-term graft loss in kidney transplant patients.
Methods. Darbepoetin alfa (DA) and carbamylated nonerythropoietic derivative of erythropoietin (CEPO) protective effects were evaluated in a model of I/R injury after kidney transplantation in both syngeneic and allogeneic combinations. The effects of wortmannin (phosphorylated Akt [p-Akt] inhibitor) administration were also investigated. Serum creatinine was evaluated at 16, 24, 48 hr and at 4 and 7 days posttransplant. Animals were killed 24 hr or 7 days after transplant and kidneys were processed for histological analysis, immunohistochemistry assessment of erythropoietin receptor (EPOR) and β-common chain receptor expression, granulocyte infiltration, nitrotyrosine staining, p-Akt expression, peritubular capillary (PTC) density, apoptosis, antioxidant, and antiapoptotic gene expression.
Results. DA and CEPO significantly reduced serum creatinine, tubular injury, tubular nitrotyrosine staining, and prevented I/R-induced tubular apoptosis, but only when given both to the donor and to the recipient. DA and CEPO cytoprotection was associated with prevention of I/R-induced drop of p-Akt expression in tubuli, and almost complete preservation of capillary density in the tubulointerstitium of the graft. CEPO was more effective than DA in reducing tubular oxidative stress and preserving PTCs.
Conclusion. DA and CEPO when given both to the donor and to the recipient, prevented renal graft dysfunction, tubular oxidative stress, and apoptosis after I/R injury in kidney transplantation. Their cytoprotection was mediated by tubular p-Akt activation and PTC density preservation.
[show abstract][hide abstract] ABSTRACT: Dendritic cells (DCs) are the most potent antigen-presenting cells and play a crucial role by modulating the T cell immune response against infective agents, tumour antigens and alloantigens. The current study shows that differentiating bone marrow (BM)-derived DCs but not fully differentiated DCs are targets of erythropoietin (EPO). Indeed, DCs emerging from rat bone marrow, but not splenic DCs, express the EPO receptor (Epo-R) and respond to EPO stimulation displaying a more activated phenotype with increased CD86, CD40 and interleukin (IL)-12 expression levels and a higher allostimulatory capacity on T cells than untreated DCs. Moreover, results here presented show that EPO up-regulates Toll-like receptor (TLR)-4 in differentiating DCs rendering these cells more sensitive to stimulation by the TLR-4 ligand lipopolysaccharide (LPS). Indeed, DCs treated with EPO and then stimulated by LPS were strongly allostimulatory and expressed CCR7, CD86, CD40, IL-12 and IL-23 at higher levels than those observed in DCs stimulated with LPS alone. It is tempting to speculate that EPO could act as an additional danger signal in concert with TLR-4 engagement. Thus, EPO, beyond its erythropoietic and cytoprotective effects, turns out to be an immune modulator.
[show abstract][hide abstract] ABSTRACT: Ischemia/reperfusion (I/R) injury is an important cause of renal graft dysfunction in humans. Increases in cold and warm ischemia times lead to a higher risk of early post-transplant complications including delayed graft function and acute rejection. Moreover, prolonged cold ischemia is a predictor of long-term kidney graft loss. The protective effect of rabbit anti-rat thymocyte immunoglobulin (rATG) was evaluated in a rat model of I/R injury following syngeneic kidney transplantation. Serum creatinine concentration was evaluated at 16 h and 24 h post-transplant. Animals were sacrificed 24 h post-transplant for evaluation of histology, infiltrating leukocytes, nitrotyrosine staining, and apoptosis. rATG was effective in preventing renal function impairment, tissue damage and tubular apoptosis associated with I/R only when was given 2 h before transplantation but not at the time of reperfusion. Pretransplant rATG treatment of recipient animals effectively reduced the amount of macrophages, CD4(+), CD8(+) T cells and LFA-1(+) cells infiltrating renal graft subjected to cold ischemia as well as granzyme-B expression within ischemic kidney. On the other hand, granulocyte infiltration and oxidative stress were not modified by rATG. If these results will be translated into the clinical setting, pretransplant administration of Thymoglobuline(®) could offer the additional advantage over peri-transplant administration of limiting I/R-mediated kidney graft damage.
Transplant International 05/2011; 24(8):829-38. · 3.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: Acute kidney injury (AKI) diagnosis is based on an increase in serum creatinine or a decrease in urine output. To be effective, treatment of AKI should be started very early after the insult and well before the rise of serum creatinine. Thus, sensitive biologic markers of renal tubular injury in AKI are strongly needed. Hu et al. suggest that Klotho could be a novel biomarker and therapeutic target of ischemia-induced AKI.
Kidney International 12/2010; 78(12):1208-10. · 7.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: Organ transplantation has proven to be an effective therapeutic for a wide variety of disease states, but the chronic immunosuppression required for allograft survival increases the risk for infection and neoplasia. In the past 50 years, a wealth of experimental data has been accumulated relating to strategies to preserve function and prolong graft survival. These strategies operate by inducing peripheral or central tolerance to the allograft, with protocols based on regulatory T cell (Treg) induction as the most promising ones. However, as these protocols move into the clinic, there is recognition that little is known as to their efficacy when confronted with the human immune system: preexisting memory T cells and "heterologous immunity" in antigen-experienced humans but not in immunologically naïve rodents, infections and early activation of innate immune response and the related inflammation-induced cytokine milieu that inhibit Treg activity while augmenting the T effector response, all pose significant barriers to tolerance induction. A better understanding of the cellular and molecular mechanisms by which memory T cells and innate immunity modulate transplant tolerance and detailed immunologic studies of the rare "spontaneously tolerant" patients may lead to development of combined strategies that target and modulate the immune system at multiple levels.
Journal of nephrology 03/2010; 23(3):263-70. · 2.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Members of the TLR/IL-1R superfamily mediate ischemia/reperfusion injury and initiate immune response in transplanted organs. In this study, we tested the hypothesis that Toll-IL-1R8 (TIR8), a negative regulator of TLR/IL-1R highly expressed in the kidney, modulates immune cell activation underlying kidney rejection. In a mouse model of fully mismatched kidney allotransplantation in which the graft is spontaneously accepted, intragraft Tir8 expression was enhanced compared with naive kidneys. Targeted deletion of Tir8 in the graft exerted a powerful antitolerogenic action leading to acute rejection. Similarly, in a mouse model of kidney graft acceptance induced by costimulation blockade, most Tir8(-/-) grafts were acutely rejected. Despite similar levels of TLR4, IL-1R, and their ligands, the posttransplant ischemia/reperfusion-induced inflammatory response was more severe in Tir8(-/-) than in Tir8(+/+) grafts and was followed by expansion and maturation of resident dendritic cell precursors. In vitro, Tir8(-/-) dendritic cell precursors acquired higher allostimulatory activity and released more IL-6 upon stimulation with a TLR4 ligand and TNF-alpha than Tir8(+/+) cells, which may explain the increased frequency of antidonor-reactive T cells and the block of regulatory T cell formation in recipients of a Tir8(-/-) kidney. Thus, TIR8 acts locally as a key regulator of allogeneic immune response in the kidney. Tir8 expression and/or signaling in donor tissue are envisaged as a novel target for control of innate immunity and amelioration of graft survival.
The Journal of Immunology 10/2009; 183(7):4249-60. · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: The role of dendritic cells (DC) that accumulate in the renal parenchyma of non-immune-mediated proteinuric nephropathies is not well understood. Under certain circumstances, DC capture immunologically ignored antigens, including self-antigens, and present them within MHC class I, initiating an autoimmune response. We studied whether DC could generate antigenic peptides from the self-protein albumin. Exposure of rat proximal tubular cells to autologous albumin resulted in its proteolytic cleavage to form an N-terminal 24-amino acid peptide (ALB1-24). This peptide was further processed by the DC proteasome into antigenic peptides that had binding motifs for MHC class I and were capable of activating syngeneic CD8+ T cells. In vivo, the rat five-sixths nephrectomy model allowed the localization and activation of renal DC. Accumulation of DC in the renal parenchyma peaked 1 wk after surgery and decreased at 4 wk, concomitant with their appearance in the renal draining lymph nodes. DC from renal lymph nodes, loaded with ALB1-24, activated syngeneic CD8+ T cells in primary culture. The response of CD8+ T cells of five-sixths nephrectomized rats was amplified with secondary stimulation. In contrast, DC from renal lymph nodes of five-sixths nephrectomized rats treated with the proteasomal inhibitor bortezomib lost their capacity to stimulate CD8+ T cells in primary and secondary cultures. These data suggest that albumin can be a source of potentially antigenic peptides upon renal injury and that renal DC play a role in processing self-proteins through a proteasome-dependent pathway.
Journal of the American Society of Nephrology 01/2009; 20(1):123-30. · 8.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background. T cell stimulation by alloantigens is followed by cell cycle progression, an event that is critically dependent on cyclin-dependent kinases.
Methods. We conducted a study to evaluate whether the cyclin-dependent kinase inhibitor seliciclib affected rat lymph node cells (LNc) activation and proliferation induced by either concanavalin A or allogeneic splenocytes in vitro and studied the mechanisms underlying the suppressive effect. We also investigated the immunosuppressive properties of seliciclib in vivo.
Results. Seliciclib completely inhibited in vitro proliferation of LNc and CD8+ T cells, in response to either concanavalin A or allogeneic splenocytes. The percentage of activated LNc was lower in mixed leukocyte reactions (MLR) added with seliciclib than in MLR added with vehicle. The percentages of viable and apoptotic cells at the end of MLR with seliciclib were comparable to those of MLR with vehicle. LNc pre-exposed in MLR to seliciclib did not respond to further stimulation with alloantigens, and neither IL-2 nor IL-15 restored proliferation. These data indicate that the inhibitory effect of seliciclib on T cell alloreactivity is not because of cytotoxic effect but is associated with induction of profound T cell anergy. LNc harvested at the end of the primary MLR with seliciclib did not suppress the proliferation of syngeneic LNc cells toward allogeneic splenocytes, thus excluding that seliciclib induced the formation of regulatory cells. Finally, seliciclib partially prolonged grafted animal survival in a rat model of fully major histocompatibility complex-mismatched kidney transplantation.
Conclusions. Altogether these results document that seliciclib regulates lymphocyte reactivity and may exert an immunosuppressive effect in vivo in the setting of transplantation.
[show abstract][hide abstract] ABSTRACT: Allogeneic immune responses are modulated by a subset of host T cells with regulatory function (Treg) contained within the CD4(+)CD25(high) subset. Evidence exists that Treg expand after peritransplantation lymphopenia, inhibit graft rejection, and induce and maintain tolerance. Little, however, is known about the role of Treg in the clinical setting. IL-2 and activation by T cell receptor engagement are instrumental to generate and maintain Treg, but the influence of immunosuppressants on Treg homeostasis in humans in vivo has not been investigated. This study monitored Treg phenotype and function during immune reconstitution in renal transplant recipients who underwent profound T cell depletion with Campath-1H and received sirolimus or cyclosporine (CsA) as part of their maintenance immunosuppressive therapy. CD4(+)CD25(high) cells that expressed FOXP3 underwent homeostatic peripheral expansion during immune reconstitution, more intense in patients who received sirolimus than in those who were given CsA. T cells that were isolated from peripheral blood long term after transplantation were hyporesponsive to alloantigens in both groups. In sirolimus- but not CsA-treated patients, hyporesponsiveness was reversed by Treg depletion. T cells from CsA-treated patients were anergic. Thus, lymphopenia and calcineurin-dependent signaling seem to be primary mediators of CD4(+)CD25(high) Treg expansion in renal transplant patients. These findings will be instrumental in developing "tolerance permissive" immunosuppressive regimens in the clinical setting.
Journal of the American Society of Nephrology 04/2007; 18(3):1007-18. · 8.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: We previously documented that rat bone marrow-derived dendritic cells (DCs), transfected with an adenovirus encoding a dominant negative form of IKK2 (dnIKK2), have impaired allostimulatory capacity and generate CD4 T cells with regulatory function. Here we investigate the potency, the phenotype, and the mechanism of action of dnIKK2-DC-induced regulatory cells and we evaluated their tolerogenic properties in vivo.
Brown Norway (BN) transfected dnIKK2-DCs were cultured with Lewis (LW) lymphocytes in primary mixed lymphocyte reaction (MLR). CD4 T cells were purified from primary MLR and incubated in secondary coculture MLR with LW lymphocytes. Phenotypic characterization was performed by fluorescence-activated cell sorting and real-time polymerase chain reaction. The tolerogenic potential of CD4 T cells pre-exposed to dnIKK2-DCs was evaluated in vivo in a model of kidney allotransplantation.
CD4 T cells pre-exposed to dnIKK2-DCs were CD4CD25 and expressed interleukin (IL)-10, transforming growth factor-beta, interferon-gamma, IL-2, and inducible nitric oxide synthase (iNOS). These cells (dnIKK2-Treg), cocultured (at up to 1:10 ratio) with a primary MLR, suppressed T-cell proliferation to alloantigens. The regulatory effect was cell-to-cell contact-independent since it was also observed in a transwell system. A nitric oxide synthase inhibitor significantly reverted dnIKK2-Treg-mediated suppression, whereas neutralizing antibodies to IL-10 and TGF-beta had no significant effect. DnIKK2-Treg given in vivo to LW rats prolonged the survival of a kidney allograft from BN rats (the donor rat strain used for generating DCs).
DnIKK2-Treg is a unique population of CD4CD25 T cells expressing high levels of iNOS. These cells potently inhibit T-cell response in vitro and induce prolongation of kidney allograft survival in vivo.
[show abstract][hide abstract] ABSTRACT: Immature dendritic cells (DC), characterized by low expression of both major histocompatibility complex class II antigens and co-stimulatory molecules, can be instrumental in the induction of peripheral tolerance. Because nuclear factor (NF)-kappa B is central to DC maturation, the authors engineered DC with an adenoviral vector (Adv) encoding for a kinase-defective dominant negative form of IKK2 (dnIKK2) to block NF-kappa B activation and inhibit DC maturation.
DC were obtained by culturing bone marrow from Brown Norway (BN) rats with granulocyte-macrophage colony-stimulating factor and interleukin-4 for 11 days. To block NF-kappa B activation, at day 9, cells were transfected with AdV-dnIKK2. At day 11, cells were used as stimulators in primary mixed leukocyte reaction (MLR) with naive Lewis rat lymphocytes as responders. CD4+ T cells were purified from primary MLR and tested in secondary MLR with allogeneic mature DC and in co-culture MLR with naive lymphocytes. The tolerogenic potential of dnIKK2-DC was evaluated in vivo in a model of rat kidney allotransplantation.
DnIKK2-DC were immature and lacked any allostimulatory activity. T cells preexposed to allogeneic dnIKK2-DC were hyporesponsive to a secondary stimulation with mature DC and acquired potent regulatory properties, inhibiting naive T-cell proliferation toward allogeneic stimuli. Pretransplant infusion of allogeneic donor dnIKK2-DC prolonged the survival of a kidney allograft from the same allogeneic donor, without the need for immunosuppressive therapy.
Allogeneic DC, rendered immature by dnIKK2 transfection, induce in vitro differentiation of naive T cells into CD4+ T-regulatory cells, effective at low ratios with target cells, rendering them applicable for cellular therapy of immune-mediated abnormalities and for preventing transplant rejection.
[show abstract][hide abstract] ABSTRACT: It was suggested that maintenance of tolerance to organ transplantation may depend on the formation of T regulatory cells.
Lewis (LW) rats were made tolerant to a Brown Norway kidney by pretransplant donor peripheral blood mononuclear cells (PBMC) infusion. At greater than 90 days after transplantation, lymph node cells (LN) and graft-infiltrating leukocytes (GIL) alloreactivity was tested in mixed lymphocyte reaction (MLR), coculture, and transwell experiments. GIL phenotype was analyzed by FACS. mRNA expression of cytokines and other markers was analyzed on CD4+ T cells from LN. The tolerogenic potential of tolerant cells in vivo was evaluated by adoptive transfer.
Tolerant LN cells showed a reduced proliferation against donor stimulators but a normal anti-third-party alloreactivity. In coculture, these cells inhibited antidonor but not antithird-party reactivity of naïve LN cells. Interleukin (IL)-10 and FasL mRNA expression was up-regulated in tolerant CD4+ T cells, but an anti-IL-10 monoclonal antibody (mAb) only partially reversed their inhibitory effect. Immunoregulatory activity was concentrated in the CD4+ CD25+ T-cell subset. In a transwell system, tolerant T cells inhibited a naïve MLR to a lesser extent than in a standard coculture. Regulatory cells transferred tolerance after infusion into naïve LW recipients. CD4+ T cells isolated from tolerized grafts were hyporesponsive to donor stimulators and suppressed a naïve MLR against donor antigens.
Donor-specific regulatory T cells play a role in tolerance induction by donor PBMC infusion. Regulatory activity is concentrated in the CD4+ CD25+ subset and requires cell-to-cell contact. Regulatory CD4+ T cells accumulate in tolerized kidney grafts where they could exert a protective function against host immune response.
[show abstract][hide abstract] ABSTRACT: It is now well recognized that regulatory T cells (Treg) play a central role in the control of both reactivity to self-antigens and alloimmune response. Several subsets of Treg with distinct phenotypes and mechanisms of action have now been identified. They constitute a network of heterogeneous CD4+ or CD8+T cell subsets and other minor T cell populations such as nonpolymorphic CD1d-responsive natural killer T cells. Treg not only play a main role in maintaining self-tolerance and preventing autoimmune disease but can also be induced by tolerance protocols and seemed to play a key role in preventing allograft rejection, as demonstrated in many animal models. Of particular interest, in stable transplant patients, CD4+CD25+ and CD8+CD28- Treg have been recently shown to modulate immune response toward donor antigens in the indirect and direct pathway, respectively. This finding raises the possibility that such Treg also have a role in the induction or maintenance of transplant tolerance in humans.
Contributions to nephrology 02/2005; 146:121-31. · 1.49 Impact Factor
[show abstract][hide abstract] ABSTRACT: Purpose of review: There is increasing evidence that regulatory T cells play a central role in the control of both reactivity to self-antigens and alloimmune response. This review focuses on the importance of regulatory T cells in clinical transplantation as a marker of hyporesponsiveness against donor antigens and as a potential therapeutic tool for tolerance induction.
Recent findings: Several subsets of regulatory T cells with distinct phenotypes and mechanisms of action have now been identified. They constitute a network of heterogeneous CD4+ or CD8+ T cell subsets and other minor T-cell populations with mechanisms of action that can be cell-contact dependent or independent. Considerable progress has been made in characterization of regulatory T cells, such as identification of FoxP3 as a specific marker. Regulatory T cells not only play a main role in maintaining self tolerance and preventing autoimmune disease, but can also be induced by tolerance protocols and seem to play a key role in preventing allograft rejection, as demonstrated in many animal models. Of particular interest, in stable transplant patients CD4+CD25+ and CD8+CD28- regulatory T cells have been recently shown to modulate immune response toward donor antigens in the indirect and direct pathway, respectively. This finding raises the possibility that such regulatory T cells also have a role in induction or maintenance of transplant tolerance in humans.
Summary: Regulatory T cells have been shown to be an essential tool by which the immune system can actively control immune responses. Future developments of transplantation research would probably have regulatory T cells as protagonists for immunologic monitoring as well as for induction of transplant tolerance.
Current Opinion in Organ Transplantation 08/2004; 9(3):301-306. · 3.27 Impact Factor
[show abstract][hide abstract] ABSTRACT: Ischemia-reperfusion injury after organ transplantation is a major cause of delayed graft function. Prevention of post-transplant ischemia acute renal failure is still elusive.
The present study was designed to examine whether propionyl-l-carnitine, an acyl derivative of carnitine involved in fatty acid oxidation pathway and adenosine 5'-triphosphate (ATP) generation of mitochondria, prevented renal function deterioration and structural injury induced by ischemia-reperfusion in an ex vivo rat model of isolated perfused kidney (IPK) preparation and in vivo in a model of syngeneic kidney transplantation.
In the model of ischemia (20 or 40 min)/reperfusion (90 or 70 min) in IPK, untreated kidneys showed a marked reduction of glomerular filtration rate (GFR) and renal perfusate flow (RPF) as compared to baseline, when perfusion was established by restoring effective perfusion pressure to 100 mm Hg. Exposure of kidneys to propionyl-l-carnitine before establishing the ischemia insult to tissue, largely prevented renal function impairment. Pre-exposure of ischemic kidneys to propionyl-l-carnitine largely reduced the percent of lactate dehydrogenase (LDH), a cell injury marker, released into the perfusate after reperfusion as compared to untreated ischemic kidneys. Histologic findings showed very mild post-ischemic lesions in kidneys exposed to propionyl-l-carnitine as compared to untreated ischemic kidneys. Immunohistochemical detection of 4-hydroxynonenal protein adduct, a major product of lipid peroxidation, was very low in kidney infused with propionyl-l-carnitine and exposed to ischemia/reperfusion as compared to untreated ischemic kidneys. ATP levels were not affected by propionyl-l-carnitine treatment. Renal function of kidneys exposed for four hours to cold Belzer UW solution added with propionyl-l-carnitine and transplanted to binephrectomized recipients was largely preserved as compared to untreated ischemic grafts. Propionyl-l-carnitine almost completely prevented polymorphonuclear cell graft infiltration and reduced tubular injury at 16 hours post-transplant.
These data indicate that propionyl-l-carnitine is of value in preventing decline of renal function that occurs during ischemia-reperfusion. The beneficial effect of propionyl-l-carnitine possibly relates to lowering lipid peroxidation and free radical generation that eventually results in the preservation of tubular cell structure. The efficacy of propionyl-l-carnitine to modulate ischemia-reperfusion injury in these models opens new perspectives for preventing post-transplant delayed graft function.
Kidney International 04/2002; 61(3):1064-78. · 7.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study found that pretransplant infusion of donor peripheral blood leukocytes, either total leukocytes (peripheral blood leukocytes) or peripheral blood mononuclear cells (PBMC), under appropriate immunomodulating conditions was more effective than donor bone marrow (BM) in prolonging the survival of rats that received kidney grafts. A higher percentage of MHCII(+) cells was found in donor PBMC than in BM cells, and depletion of MHCII(+) cells from donor PBMC abolished their tolerogenic potential. By the analysis of microchimerism in rats infused with donor cells and killed at different time points thereafter, the better tolerogenic potential of leukocyte infusion related to a higher capability of these cells to engraft the recipient thymus. PCR analysis on OX6-immunopurified cells revealed the presence of donor MHCII(+) cells in the thymus of these animals. The role of intrathymic microchimerism was reinforced by findings that thymectomy at the time of transplant prevented tolerance induction by donor leukocytes. Donor DNA was found in the thymus of most long-term graft animals that survived, but in none of those that rejected their grafts. The presence of intrathymic microchimerism correlated with graft survival, and microchimerism in other tissues was irrelevant. PCR analysis of DNA from thymic cell subpopulations revealed the presence of donor MHCII(+) cells in the thymus of long-term surviving animals. Thus, in rats, donor leukocyte infusion is better than donor BM for inducing graft tolerance, defined by long-term graft survival, donor-specific T cell hyporesponsiveness, and reduced interferon gamma production. This effect appears to occur through migration of donor MHCII(+) cells in the host thymus.
Journal of the American Society of Nephrology 01/2002; 12(12):2815-26. · 8.99 Impact Factor