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We aimed to determine the role of cytomegalovirus (CMV)‐infected donor cells in the development of a CMV‐specific immune response in kidney transplant recipients. We assessed the CMVpp65‐specific immune response by using interferon‐ɣ ELISPOTand dextramers in peripheral blood mononuclear cells from 115 recipients (D+R− 31, D+R + 44, D−R + 40) late after transplantation (mean 59 ± 42 months). Receiving a kidney from a D+ donor resulted in a higher number of IFN‐ɣ‐producing anti‐CMVT cells (P= .004). This effect disappeared with the absence of shared HLAclass I specificities between donors and recipients (P= .430). To confirm the role of donor cells in stimulating the expansion of newly developed CMV‐specific CD8+T cells after transplantation, we compared the number of HLA‐A2–restricted CMV‐specific CD8+T cells in primo‐infected recipients who received an HLA‐A2 or non–HLA‐A2 graft. The median of anti‐CMVpp65 T cells restricted by HLA‐A2 was very low for patients who received a non–HLA‐A2 graft vs an HLA‐A2 graft (300 [0‐14638] vs. 17972 [222‐85594] anti‐CMVpp65 CD8+T cells/million CD8+T cells, P= .001). This adds new evidence that CMV‐infected kidney donor cells present CMVpeptides and drive an inflation of memory CMV‐specific CD8+T cells, likely because of frequent CMVreplications within the graft. Donor cytomegalovirus (CMV) infection affects the CMV‐specific immune response and donor‐shared HLA‐I is crucial for the development of CMV‐specific CD8+ T cells, suggesting that CMV‐infected kidney donor cells present CMV peptides and drive an inflation in memory CMV‐specific T cells.

We aimed to determine the role of cytomegalovirus (CMV)-infected donor cells in the development of a CMV-specific immune response in kidney transplant recipients. We assessed the CMV pp65-specific immune response by using interferon-ɣ ELISPOT and dextramers in peripheral blood mononuclear cells from 115 recipients (D+R− 31, D+R + 44, D−R + 40) late after transplantation (mean 59 ± 42 months). Receiving a kidney from a D+ donor resulted in a higher number of IFN-ɣ-producing anti-CMV T cells (P= .004). This effect disappeared with the absence of shared HLA class I specificities between donors and recipients (P= .430). To confirm the role of donor cells in stimulating the expansion of newly developed CMV-specific CD8+T cells after transplantation, we compared the number of HLA-A2–restricted CMV-specific CD8+T cells in primo-infected recipients who received an HLA-A2 or non–HLA-A2 graft. The median of anti-CMV pp65 T cells restricted by HLA-A2 was very low for patients who received a non–HLA-A2 graft vs an HLA-A2 graft (300 [0-14638] vs. 17972 [222-85594] anti-CMV pp65 CD8+T cells/million CD8+T cells, P= .001). This adds new evidence that CMV-infected kidney donor cells present CMV peptides and drive an inflation of memory CMV-specific CD8+T cells, likely because of frequent CMV replications within the graft.

The high frequency of allogeneic reactive CD8+ T cells in human and their resistance to immunosuppression might be one of the reasons why successful tolerance-inducing strategies in rodents have failed in primates. Studies on the requirement for T-helper cells in priming CD8+ T-cell responses have led to disparate findings. Recent studies have reported CD8+-mediated allograft rejection independently of T-helper cells; however, the mechanisms that govern the activation of these T cells are far from being elucidated. In this study, we demonstrated that lipopolysaccharide-treated dendritic cells (DCs) were able to induce proliferation and cytotoxic activity of allogeneic CD8+ T cells independently of CD4+ T cells, while adding mycophenolic acid (MPA) to LPS abolished this capacity and resulted in anergic CD8+ T cells that secreted high levels of interleukin-4 (IL-4), IL-5, IL-10, and transforming growth factor-β. Interestingly, we demonstrated that MPA inhibited the LPS-induced synthesis of tumor necrosis factor-α, IL-12, and interferon-γ (IFN-γ) in DCs. Importantly, we found that adding exogenous IFN-γ to MPA restored both the synthesis of cytokines and the ability to activate CD8+ T cells. However, adding IL-12 or tumor necrosis factor-α had no effect. These results suggest that IFN-γ has an important role in licensing DCs to prime CD4-independent CD8 allogeneic T cells via an autocrine loop.

Indirect effects of cytomegalovirus (CMV) in transplantation are of three types increase in systemic immunosuppression, increased risk of malignancy (especially Epstein–Barr virus-related B-cell lymphoproliferative disease), and the possible contribution to allograft injury. Despite modern and potent antiviral drugs, the real impact of CMV in transplantation, especially kidney transplantation, remains a challenge because many confounding factors arise when analyzing this question.

Depending on their degree of maturation, costimulatory molecule expression, and cytokine secretion, dendritic cells (DC) can induce immunity or tolerance. DC treated with mycophenolic acid during their maturation (MPA‐DC) have a regulatory phenotype and may therefore provide a new approach to induce allograft tolerance. Purified CD4+T cells stimulated in a human in vitro model of mixed culture by allogeneic MPA‐DC displayed much weaker proliferation than T cells activated by mature DC and were anergic. This hyporesponsiveness was alloantigen‐specific. Interestingly, T cells stimulated by MPA‐DC during long‐term coculture in four 7‐day cycles displayed potent, suppressive activity, as revealed by marked inhibition of the proliferation of naive and preactivated control T cells. These regulatory T cells (Tregs) appeared to have antigen specificity and were contact‐dependent. Tregs induced by MPA‐DC were CD25+glucocorticoid‐induced TNFR+CTLA‐4+CD95+, secreted IL‐5 and large amounts of IL‐10 and TGF‐β, and displayed enhanced forkhead box p3 expression. These results obtained in vitro demonstrate that human MPA‐DC can induce allospecific Tregs that may be exploited in cell therapy to induce allograft tolerance.

Cytomegalovirus (CMV) infection is associated with a significant rate of morbidity after organ transplantation. The genetic factors influencing its occurrence have been little investigated. IL-12 plays a crucial role in anti-infectious immune responses, especially by stimulating IFNγ production. An A-to-C single nucleotide polymorphism (SNP) within the 3′-untranslated region of the IL-12p40 gene has been characterized and was reported to be both functionally and clinically relevant. However, the impact of this single nucleotide polymorphism on events after organ transplantation has never been reported.

Because histopathologic criteria cannot always predict the pathogenesis and response to curative antirejection therapy, new hope derives from the molecular analysis of intragraft immunologic markers. We studied whether the cutoff of intragraft expression level of T-cell activation markers may define subgroups of acute rejection differing either in type of rejection or clinical outcome.

Pilot clinical studies have shown that the rat anti-human-CD2 monoclonal antibody, LoCD2a/BTI-322, can efficiently prevent and treat acute kidney rejection. However, the in vivo mechanism by which it prevents allograft rejection has not been studied. BTI-322 and its humanized form have been shown to mediate in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) against CD2cells through the activation of monocytes or natural killer (NK) cells.

Acute rejections are scored according to three main criteria: vasculitis, tubulitis and interstitial infiltration as defined in the Banff classification. Typically, B cells account for <8% of the infiltrates and oedema is limited. The clinical significance of severe interstitial oedema and plasma cell-rich infiltrates (OPcR) are still a matter of debate.

Abstract Due to the nephrotoxicity of cyclosporin A (CsA), its benefit on long‐term graft survival remains controversial, especially in low‐risk patients. Here we report the 12‐year results of a calcineurin‐inhibitor‐free regimen. One hundred and seventeen low‐risk kidney recipients were prospectively randomized to maintenance therapy with either a combination of azathioprine and prednisone (group NoCsA, n= 58), or with cyclosporine, azathioprine, and prednisone (group CsA, n= 59). Both groups received induction therapy with anti‐lymphocyte globulins (ALG). Twelve‐year patient survival was 75% and 82.5% in the CsA and NoCsA groups, respectively [P= not significant (NS)]. Twelve‐year graft survival was 59% and 56% (P= NS) in the CsA and NoCsA groups, respectively (NS). Transplant rejection rates were similar in both groups. Mean serum creatinine levels after 10 years were 161 and 136 μmol/I in the CsA and NoCsA groups, respectively. Rejection‐free patients of the CsA group had poorer renal function (168 μmol/I) than those of the NoCsA group (121 μmol/I; P= 0.0060). We concluded that a 12‐year graft survival of 56% and a graft half‐life of 15 years can be achieved without the primary use of a calcineurin inhibitor in low‐risk patients receiving ALG. Patients treated with CsA had poorer graft function at 12 years.

Abstract. Due to the nephrotoxicity of cyclosporin A (CsA), its benefit on long-term graft survival remains controversial, especially in low-risk patients. Here we report the 12-year results of a calcineurin-inhibitor-free regimen. One hundred and seventeen low-risk kidney recipients were prospectively randomized to maintenance therapy with either a combination of azathioprine and prednisone (group NoCsA, n=58), or with cyclosporine, azathioprine, and prednisone (group CsA, n=59). Both groups received induction therapy with anti-lymphocyte globulins (ALG). Twelve-year patient survival was 75% and 82.5% in the CsA and NoCsA groups, respectively [P= not significant (NS)]. Twelve-year graft survival was 59% and 56% (P=NS) in the CsA and NoCsA groups, respectively (NS). Transplant rejection rates were similar in both groups. Mean serum creatinine levels after 10 years were 161 and 136 μmol/l in the CsA and NoCsA groups, respectively. Rejection-free patients of the CsA group had poorer renal function (168 μmol/l) than those of the NoCsA group (121 μmol/l; P=0.0060). We concluded that a 12-year graft survival of 56% and a graft half-life of 15 years can be achieved without the primary use of a calcineurin inhibitor in low-risk patients receiving ALG. Patients treated with CsA had poorer graft function at 12 years.

The sensitive cross-match (XM) techniques that have been introduced for clinical transplantation can detect anti-donor immune reactivity despite a negative standard National Institute of Health (NIH) cross-match. One of them uses anti-kappa human light chain globulins (AHG). But there is some discussion about the clinical consequences of a positive AHG-XM in the historical sera that became negative in the sera collected just before the transplantation (pretransplant sera). This study was intended to assess the risk of kidney graft failure associated with a positive historic but negative pretransplant AHG-XM in allosensitized patients having a negative historic NIH-XM.

The aim of this study was to compare the efficacy and safety of induction treatment with antithymocyte globulins (ATG) followed by tacrolimus therapy with immediate tacrolimus therapy in renal transplant recipients.

We describe a 36-year-old man who presented with hypocomplementemic urticarial vasculitis syndrome (HUVS) with severe renal involvement. Despite steroid therapy, the patient developed end-stage renal disease (ESRD) leading to chronic hemodialysis therapy. Renal transplantation was performed after hemodialysis therapy (secondary), and the patient developed a typical HUVS relapse 9 months after transplantation despite conventional immunosuppressive therapy that was successfully treated with plasma exchange. This case shows for the first time that HUVS can induce severe renal involvement responsible for ESRD and that HUVS can relapse after renal transplantation. It also suggests that plasma exchange therapy may be of value for rapidly controlling the clinical symptoms.

Objectives: To study the pharmacologic activity of mycophenolate mofetil in stable kidney transplant recipients receiving mycophenolate mofetil therapy for different periods from 2 months to 3 years.Methods: Seventeen patients were enrolled during a 9-month period. Blood samples were collected before administration and ½, 1, 2, 4, and 6 hours after administration. Mycophenolic acid, the active metabolite of mycophenolate mofetil, was measured in plasma with use of the enzyme multiplication immunoassay technique (EMIT) assay and the activity of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo biosynthesis of purines inhibited by mycophenolate mofetil, was determined in whole blood by the estimation of the 3H-release from [2,8-3H]-hypoxanthine.Results: As the length of mycophenolate mofetil therapy increased, the inhibitory effect of mycophenolate mofetil on IMPDH activity was reduced (0.13 ± 0.03 for long-term treatment versus 0.46 ± 0.06 for short-term treatment; P = .0006) and a stimulatory effect of mycophenolate mofetil on IMPDH activity was observed (1.16 ± 0.56 for long-term treatment, versus 0.03 ± 0.01 for short-term treatment; P < .0001). These modifications of IMPDH activity were associated with fluctuations in the pharmacokinetics of mycophenolic acid.Conclusion: Long-term treatment with mycophenolate mofetil was associated with an induction of IMPDH activity. Such induction could be deleterious if it is followed by a restoration or a stimulation of the proliferative capacity of lymphocytes. These results strongly suggest that the place of mycophenolate mofetil in long-term treatment of kidney transplant patients needs to be carefully assessed.

The combination at the nanosize level of inorganic and organic components in a single material makes accessible an immense new area of materials science. Among other soft chemistry processes, sol-gel chemistry offers a versatile access to chemically designed new hybrid organic-inorganic materials. Yet, it might be inappropriate to prepare “model” hybrid materials, in which the structure of the organic and inorganic domains, together with those of their interface, are perfectly defined. Such systems, required to understand, optimize, and control the structure-properties relationship, can be alternatively prepared by assembling well-defined preformed inorganic nanobuilding blocks.The molecular structures and syntheses of two types of organotin oxo-clusters, {(RSn)12O14(OH)6}2+(X−)2(“Tin-12”) and {RSnO(O2CR′)}6(“Tin-6”) are presented. Various strategies to assemble them are discussed to illustrate the versatility of such nanobuilding blocks in the synthesis of hybrid systems with iono-covalent or ionic organic/inorganic interfaces.

Acute graft pyelonephritis is a common complication in renal transplant recipients. The consequences of this complication on kidney allograft survival remain controversial. Bacterial infection is likely to activate the immune system, potentially leading to acute or chronic rejection. Here, we report for the first time two documented cases of acute rejection occurring shortly after acute graft pyelonephritis, suggesting that pyelonephritis can initiate acute rejection. The immunologic process leading to the alloimmune response is discussed. These reports suggest that acute rejection should be questioned in case of atypical graft outcome in the context of acute graft pyelonephritis.

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