RESUMO
HIV + patients are commonly accepted for kidney transplantation. However, patients on protease inhibitor (PI)- or cobicistat (cobi)-based regimens have trouble achieving optimal tacrolimus (Tac) levels. Our study compared the ability to achieve target levels using liquid versus immediate-release capsule Tac in kidney transplant patients with HIV on PI- or cobi-based regimens. The study included four kidney transplant patients who were converted to liquid Tac due to inability to achieve acceptable drug levels on the capsule formulation. Tac trough levels were analyzed retrospectively to compare target levels before and after conversion. The individual patient time in the therapeutic range (TTR) was calculated using Rosendaal's linear interpolation method, and the difference between before and after conversion TTR was determined. In combined data, 44.63% of all Tac trough levels were within the target range after conversion to liquid Tac compared to 22.07% prior to conversion (P < .001). Furthermore, 3.31% and 7.44% of Tac trough levels were lower than 3 ng/mL or higher than 12 ng/mL, respectively, after conversion compared to 11.72% (P = .0564) and 24.14% (P < .0001) prior to conversion. The overall mean TTR was 45.1% after conversion to liquid Tac compared to 16.2% prior to conversion (P = .097). Finally, the coefficient of variation for Tac trough levels was 42.6 after conversion compared to 56.4 prior to conversion. A significantly improved ability to achieve target trough Tac levels was achieved with liquid Tac extemporaneous versus capsule formulation in kidney transplant patients with HIV taking a PI- or cobi-based regimen.
Assuntos
Infecções por HIV , Transplante de Rim , Cobicistat , Infecções por HIV/tratamento farmacológico , Humanos , Imunossupressores , Inibidores de Proteases , Estudos Retrospectivos , TacrolimoRESUMO
BACKGROUND: Immunosuppression reduction for BK viremia is associated with de novo humoral responses, which are a risk factor for rejection and graft loss. In this pilot project, we tested a protocol of immunosuppression resumption to standard dose after viral clearance for optimal protection against humoral immunity in patients undergoing treatment for BK viremia. METHODS: Thirty-six consecutive kidney transplant recipients who developed BK viremia from 7/1/2014 to 11/18/2016 underwent immunosuppression reduction. After 4 weeks of absent viremia, mycophenolate mofetil (MMF) was increased by 500mg/day every 2 weeks up to standard dosage, followed by increase of tacrolimus trough levels to 5-7 ng/mL. If viremia recurred during the increase, immunosuppression was reduced in this same stepwise fashion, with stepwise increase again after 2 months of negative viremia. RESULTS: Mean tacrolimus trough level (ng/mL) was 8.3 ± 2.7 at viremia onset, 5.3 ± 3.6 at resolution, and 5.6 ± 2.0 at study end date. Mean daily dose (mg) of MMF was 1574 ± 355 at onset, 910 ± 230 at resolution, and 1377 ± 451 at study end date. Only one patient developed low level viremia recurrence (peak 2875 copies/mL) during the period of immunosuppression resumption that ultimately resolved. CONCLUSIONS: The results of our pilot project indicate that following BK viremia resolution, resumption of standard immunosuppression can be achieved safely without BK viremia recurrence. Larger trials with long-term follow up are required to determine whether such an approach improves long-term graft survival.
Assuntos
Vírus BK , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Viremia , Humanos , Terapia de Imunossupressão , Imunossupressores , Transplante de Rim , Projetos Piloto , TacrolimoRESUMO
The outcomes of lymphocyte-depleting antibody induction therapy (LDAIT), [thymoglobulin (ATG) or alemtuzumab (ALM)] versus interleukin-2 receptor antagonist (IL-2RA) in the nonbroadly-sensitized [pretransplant calculated panel reactive antibody (cPRA), <80%] adult deceased donor kidney transplant recipients (adult-DDKTRs) are understudied. In this registry, study of 55 593 adult-DD-KTRs, outcomes of LDAIT [(ATG, N = 32 985) and (ALM, N = 9429)], and IL-2RA (N = 13 179) in <10% and 10-79% cPRA groups was analyzed. Adjusted odds ratio (aOR) of one-year biopsy-proven acute rejection (BPAR) was lower; while, aOR of 1-year composite of re-hospitalization, graft loss, or death was higher with LDAIT than IL2-RA in both cPRA groups. Adjusted odds ratio (aOR) of delayed graft function was higher with LDAIT than IL-2RA in the <10% cPRA group. Adjusted hazard ratio (aHR) of 5-year death-censored graft loss (DCGL) in both <80% cPRA groups seemed higher with ALM than other inductions [(<10% cPRA: ALM versus IL2RA, aHR = 1.11, 95% CI = 1.00-1.23 and ATG versus ALM: aHR = 0.84, 95% CI = 0.77-0.91; 10-79% cPRA: ALM versus IL2RA, aHR = 1.29, 95% CI = 1.02-1.64; and ATG versus ALM, aHR = 0.83, 95% CI = 0.70-0.98)]. Five-year aHR of death did not differ among induction therapies in both cPRA groups. In nonbroadly sensitized adult-DDKTRs, LDAIT is more protective against 1-year BPAR (not 5-year mortality) than IL-2RA; the trend of a higher 5-year DCGL risk with ALM than ATG or IL-2RA needs further investigation.
Assuntos
Transplante de Rim , Adulto , Soro Antilinfocitário/uso terapêutico , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêutico , Sistema de Registros , Estudos RetrospectivosRESUMO
High index of suspicion for adenovirus infection is required in renal graft dysfunction, especially in the setting of hematuria. Histology can mimic acute rejection, which creates a diagnostic dilemma. Tissue adenovirus immunostains, though usually reliable, may not be always positive like in our case.
RESUMO
Background: This study aimed to analyze adult kidney transplant recipients (KTRs) for the risk of new-onset diabetes after transplantation (NODAT) associated with viral serologies and immunosuppression regimens [tacrolimus (Tac) + mycophenolate (MPA), cyclosporine (CSA) + MPA, sirolimus (SRL) + MPA, SRL + CSA or SRL +Tac]. Methods: Cox regression models were used to examine the risk of NODAT in the first posttransplant year associated with: (i) CSA + MPA, SRL + MPA, SRL + MPA or SRL + Tac versus reference, Tac + MPA; (ii) pretransplant viral serology [+ or -; hepatitis B core (HBc), hepatitis C (HCV), cytomegalovirus (CMV) or Epstein Barr Virus (EBV)]; and (iii) interactions between immunosuppression regimens and the viral serology found significant in the main analysis. Results: Adult KTRs (n = 97 644) from January 1995 through September 2015 were studied. HCV+ [hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.31-1.68] or CMV+ (HR 1.12, 95% CI 1.06-1.19) serology was a risk factor and HBc+ (HR 1.04, 95% CI 0.95-1.15) or EBV+ (HR 1.06, 95% CI 0.97-1.15) serology was not a risk factor for NODAT. Regardless of associated HCV or CMV serology, risk of NODAT relative to the reference regimen (Tac + MPA) was lower with CSA + MPA [HCV-: HR 0.74, 95% CI 0.65-0.85; HCV+: HR 0.47, 95% CI 0.28-0.78; CMV-: CSA + MPA HR 0.68, 95% CI 0.54-0.86; CMV+: (CSA + MPA) HR 0.73, 95% CI 0.63-0.85] and similar with SRL + CSA or SRL + MPA. In KTRs with HCV- or CMV+ serology, SRL + Tac was associated with a higher risk of NODAT relative to reference [HCV- (HR 1.43, 95% CI 1.17-1.74) and CMV+ (HR 1.44, 95% CI 1.14-1.81), respectively]. The risk for NODAT-free graft loss was lower with Tac + MPA than the other regimens. Conclusions: Tailoring immunosuppression regimen based on HCV or CMV serology may modify the risk of developing NODAT in KTRs.
Assuntos
Diabetes Mellitus/diagnóstico , Diabetes Mellitus/tratamento farmacológico , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Viroses/sangue , Vírus/isolamento & purificação , Adolescente , Adulto , Idade de Início , Diabetes Mellitus/sangue , Diabetes Mellitus/etiologia , Feminino , Humanos , Terapia de Imunossupressão , Masculino , Pessoa de Meia-Idade , Viroses/virologia , Adulto JovemRESUMO
BACKGROUND: The risks for transplant outcomes associated with baseline viral serostatus in kidney transplant recipients (KTR) on sirolimus have not been widely studied. METHODS: We performed a cohort-study of 61 590 adult KTR in 2000 to 2013. We used Cox regression models to determine the adjusted hazard ratio (aHR) of patient death, death-censored graft loss and posttransplant malignancy associated with the baseline serostatus (+ or -: hepatitis B core [HBc], hepatitis C virus [HCV], Epstein-Barr virus [EBV], or cytomegalovirus [CMV]) in KTR on sirolimus (SRL) + mycophenolate (MPA) or SRL + tacrolimus (Tac), relative to the control-regimen: Tac + MPA. RESULTS: Compared with Tac + MPA, SRL + MPA, and SRL + Tac were associated with higher risks of 5-year mortality (aHR, 1.41; 95% CI, 1.23-1.60 and aHR, 1.59; 95% CI, 1.38-1.83, respectively) and death-censored graft loss (aHR, 1.41; 95% CI, 1.24-1.60 and aHR, 1.38; 95% CI, 1.21-1.57, respectively). In KTR with negative pretransplant EBV, CMV, HBc, or HCV serostatus, SRL + MPA not SRL + Tac was associated with a lower risk of posttransplant malignancy compared with control (aHR, 0.27; 95% CI, 0.10-0.72; aHR, 0.61; 95% CI, 0.43-0.88; aHR, 0.79; 95% CI, 0.64-0.97; and aHR, 0.80; 95% CI, 0.65-0.98, respectively, for SRL + MPA and aHR, 0.98: 95% CI, 0.52-1.80; aHR, 0.69; 95% CI, 0.46-1.06; aHR, 0.83; 95% CI, 0.66-1.06 and aHR, 0.85; 95% CI, 0.67-1.07, respectively, for SRL + Tac). In KTR with positive serostatus to any of the above viruses, SRL + MPA or SRL + Tac was not associated with a different malignancy risk compared with control. CONCLUSIONS: Compared with Tac + MPA, SRL regimens were associated with higher risks for patient death and graft loss, although SRL + MPA was associated with a lower risk for posttransplant malignancy in kidney allograft recipients with negative pretransplant HBc, HCV, EBV, or CMV serology.
Assuntos
Anticorpos Antivirais/sangue , Infecções por Citomegalovirus/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Hepatite B/imunologia , Hepatite C/imunologia , Imunossupressores/uso terapêutico , Transplante de Rim , Sirolimo/uso terapêutico , Adulto , Aloenxertos , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/mortalidade , Quimioterapia Combinada , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/mortalidade , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Hepatite B/sangue , Hepatite B/diagnóstico , Hepatite B/mortalidade , Hepatite C/sangue , Hepatite C/diagnóstico , Hepatite C/mortalidade , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias/etiologia , Razão de Chances , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Testes Sorológicos , Sirolimo/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Estados UnidosAssuntos
Cistite/diagnóstico por imagem , Cistite/microbiologia , Transplante de Rim , Infecções por Klebsiella/diagnóstico por imagem , Transplante de Pâncreas , Antibacterianos/uso terapêutico , Cistoscopia , Diagnóstico Diferencial , Disuria , Hematúria , Humanos , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
We studied registry data of 12,944 adult kidney retransplant recipients categorized by induction regimen received into antithymocyte globulin (ATG) (N = 9120), alemtuzumab (N = 1687), and basiliximab (N = 2137) cohorts. We analyzed risk factors for 1-year acute rejection (AR) and 5-year death-censored graft loss (DCGL) and patient death. Compared with the reference, basiliximab: (1) one-year AR risk was lower with ATG in retransplant recipients of expanded criteria deceased-donor kidneys (HR = 0.56, 95% CI = 0.35-0.91 and HR = 0.54, 95% CI = 0.27-1.08, resp.), while AR risk was lower with alemtuzumab in retransplant recipients with >3 HLA mismatches before transplant (HR = 0.63, 95% CI = 0.44-0.93 and HR = 0.81, 95% CI = 0.63-1.06, resp.); (2) five-year DCGL risk was lower with alemtuzumab, not ATG, in retransplant recipients of African American race (HR = 0.54, 95% CI = 0.34-0.86 and HR = 0.73, 95% CI = 0.51-1.04, resp.) or with pretransplant glomerulonephritis (HR = 0.65, 95% CI = 0.43-0.98 and HR = 0.82, 95% CI = 0.60-1.12, resp.). Therefore, specific risk factor-induction regimen combinations may predict outcomes and this information may help in individualizing induction in retransplant recipients.
RESUMO
Mesenchymal stromal cells (MSCs) have shown promise as cellular therapy in allogeneic transplantation, although the precise mechanisms underlying their benefit in clinical trials are difficult to study. We previously demonstrated that MSCs exert immunoregulatory effects in mouse bone marrow-derived dendritic cell (DC) culture. Since mouse studies do not reliably reproduce human events, we used a humanized mouse model to study the immunomodulatory effects of human MSCs on human DC immunobiology. Humanized mice were established by injection of cord blood CD34(+) cells into NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl/SzJ) (NOD scid gamma, NSG) mice. Human cells were detected in the mouse bone marrow, blood, and spleen 12weeks after transplantation. Human DCs were differentiated from humanized mouse bone marrow cells during human MSC co-culture. MSCs inhibited DC differentiation and kept DCs in an immature state as demonstrated by phenotype and function. In conclusion, humanized mouse models represent a useful method to study the function of human MSCs on human DC immunobiology.
Assuntos
Diferenciação Celular/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células-Tronco Mesenquimais/imunologia , Animais , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Animais , Células Mieloides/citologia , Células Mieloides/imunologiaRESUMO
BACKGROUND: Survival data are lacking for kidney transplant recipients with rare native end-stage renal disease (ESRD) etiologies. There is currently no large registry study comparing dialysis versus kidney transplantation survival outcomes of waitlisted adults with hemolytic uremic syndrome (HUS). MATERIALS AND METHODS: We retrospectively studied adult-HUS end-stage renal disease patients (n = 559) placed on the US kidney transplant waitlist in 1996 to 2011. We analyzed 5-year transplantation and patient survival probabilities and risk factors using Kaplan-Meier and Cox hazards models, respectively. Using similar models, waitlist and transplantation outcomes of patients with diabetes mellitus (DM), hypertension (HTN), and glomerulonephritis (GN) were analyzed, and then compared with HUS patients. RESULTS: Compared with waitlisted adult HUS patients on dialysis, 5-year mortality risks were 73% and 48% lower in recipients of living (hazard ratio [HR], 0.27, 95% confidence interval [95% CI], 0.11-0.65) and standard deceased (HR, 0.52; 95% CI, 0.29-0.94) donor kidney transplants, respectively. Mortality risks over 5 years were 44%, 50%, 54%, and 55% lower in the overall transplant recipient cohorts than in the dialysis-maintained cohorts within the HUS (HR, 0.56; 95% CI, 0.35-0.91), HTN (HR, 0.50; 95% CI, 0.48-0.52), GN (HR, 0.46; 95% CI, 0.44-0.49), and DM (HR, 0.45; 95% CI, 0.44-0.47) groups, respectively. Five-year transplantation probability in the waitlisted HUS cohort was 60% versus 42% to 49% (P < 0.001) in the DM and HTN cohorts, and 62% (P = 0.93) in the GN cohort. CONCLUSIONS: Living and standard criteria deceased donor kidney transplants provide significant survival benefit over dialysis in waitlisted adults with HUS. On the waitlist, the 5-year transplantation probability was higher in HUS than in DM and HTN patients.
Assuntos
Previsões , Síndrome Hemolítico-Urêmica/terapia , Transplante de Rim/mortalidade , Sistema de Registros , Diálise Renal , Transplantados , Listas de Espera/mortalidade , Adulto , Feminino , Florida/epidemiologia , Síndrome Hemolítico-Urêmica/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendênciasRESUMO
Reduced pretransplant blood myeloid dendritic cell (mDC) levels are associated with post-transplant BK viremia and cytomegalovirus (CMV) disease after kidney transplantation. To elucidate potential mechanisms by which mDC levels might influence these outcomes, we studied the association of mDC levels with mDC IL-12 production and T-cell level/function. Peripheral blood (PB) was studied in three groups: (i) end stage renal disease patients on hemodialysis (HD; n = 81); (ii) chronic kidney disease stage IV-V patients presenting for kidney transplant evaluation or the day of transplantation (Eval/Tx; n = 323); and (iii) healthy controls (HC; n = 22). Along with a statistically significant reduction in mDC levels, reduced CD8(+) T-cell levels were also demonstrated in the kidney disease groups compared with HC. Reduced PB mDC and monocyte-derived DC (MoDC) IL-12 production was observed after in vitro LPS stimulation in the HD versus HC groups. Finally, ELISpot assays demonstrated less robust CD3(+) INF-γ responses by MoDCs pulsed with CMV pp65 peptide from HD patients compared with HC. PB mDC level deficiency in patients with kidney disease is associated with deficient IL-12 production and T-cell level/function, which may explain the known correlation of CD8(+) T-cell lymphopenia with deficient post-transplant antiviral responses.
Assuntos
Infecções por Citomegalovirus/imunologia , Interleucina-1/metabolismo , Falência Renal Crônica/cirurgia , Transplante de Rim/métodos , Adulto , Análise de Variância , Biomarcadores/análise , Estudos de Casos e Controles , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/epidemiologia , Células Dendríticas/citologia , ELISPOT , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Transplante de Rim/efeitos adversos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Valores de Referência , Diálise Renal/efeitos adversos , Diálise Renal/métodos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapia , Estatísticas não Paramétricas , Linfócitos T/imunologia , Imunologia de Transplantes , Resultado do Tratamento , Viremia/diagnóstico , Viremia/epidemiologia , Viremia/imunologiaRESUMO
Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by the destruction of pancreatic insulin-producing ß cells by autoreactive T cells early in life. Despite daily insulin injections, patients typically develop cardiovascular and other complications; and intensive efforts are being directed toward identifying therapeutic targets to prevent the disease without directly impinging on the host defense. Fas ligand (FasL) is one potential target. Fas-FasL interactions primarily regulate T-cell homeostasis, not activation. Nevertheless, spontaneous gene mutation of Fas (called lpr mutation) or FasL (called the gld mutation) prevents autoimmune diabetes in nonobese diabetic (NOD) mice, the widely used model for T1D. Furthermore, although homozygous gld mutations cause age-dependent lymphoproliferation, limiting the gld mutation to one allele (NOD-gld/+) or treating NOD-wild-type mice with FasL-neutralizing monoclonal antibody completely prevents the disease development without causing lymphoproliferation or immune suppression. Herein, we show that the heterozygous gld mutation inhibits the accumulation of diabetogenic T cells in the pancreas, without interfering with their proliferation and expansion in the draining pancreatic lymph nodes. Pancreata from NOD-gld/+ mice contained B cells that expressed CD5 and produced IL-10, which was critical for maintenance of the disease resistance because its neutralization with an IL-10 receptor-blocking monoclonal antibody allowed accumulation of CD4 T cells in the pancreas and led to insulitis development. The results provide novel insights into the pathogenesis of T1D that could have important therapeutic implications.
Assuntos
Proteína Ligante Fas/metabolismo , Insulina/metabolismo , Interleucina-10/genética , Animais , Proliferação de Células , Separação Celular , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Genótipo , Homozigoto , Sistema Imunitário , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Mutação , Linfócitos T/citologiaRESUMO
Inflammation contributes to the pathogenesis of ischemic acute kidney injury (AKI), and T cells mediate the early phase of ischemia-reperfusion injury (IRI). The Fas/Fas ligand (FasL) pathway modulates the balance of T cell subsets in the peripheral circulation as well as multiple inflammatory responses, suggesting that FasL may mediate ischemic AKI. Here, we induced bilateral renal IRI in mice bearing a loss-of-function mutation of FasL (the gld mutation) and in wild-type mice. Compared with wild-type mice, serum creatinine was lower in gld mice (1.4 ± 0.9 mg/dl versus 2.6 ± 0.4) at 24 hours after IRI (P<0.05). In addition, gld mice had fewer TNF-α-producing T lymphocytes in the kidneys and renal lymph nodes. Furthermore, pharmacologic blockade of FasL protected the kidneys of wild-type mice from IRI. Analysis of bone marrow chimeric mice suggested that the pathogenic effect of FasL involves leukocytes; reconstitution of wild-type mice with gld splenocytes attenuated IRI. In contrast, reconstitution of gld mice with wild-type splenocytes enhanced IRI. These data demonstrate that FasL, particularly on leukocytes, mediates ischemic AKI.
Assuntos
Injúria Renal Aguda/prevenção & controle , Proteína Ligante Fas/deficiência , Leucócitos/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Injúria Renal Aguda/metabolismo , Animais , Caspase 3/metabolismo , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Linfonodos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Peroxidase/metabolismo , Traumatismo por Reperfusão/metabolismo , Baço/metabolismo , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The last several decades have witnessed a substantial decrease in the incidence of acute allograft rejection following kidney transplantation, although commensurate improvements in long-term graft function have not been realized. As a result, the primary focus of new immunosuppressive drug development has expanded to include ease of use and improved side effect profile, including reduced nephrotoxicity, in addition to the more traditional goal of improved short-term outcomes. A number of novel drugs are currently under investigation in Phase I, II, or III clinical trials, primarily to replace the nephrotoxic but highly effective calcineurin inhibitors. Belatacept is a humanized antibody that inhibits T cell costimulation and has shown encouraging results in multiple Phase II and III trials. This article reviews the mechanism of action of belatacept, as well as published and preliminary results of the Phase I-III clinical trials involving this novel immunosuppressive agent.
Assuntos
Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Abatacepte , Animais , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacologia , Imunossupressores/efeitos adversos , Imunossupressores/farmacologia , Linfócitos T/metabolismoRESUMO
BACKGROUND: Mesenchymal stromal cells (MSCs) are multipotent cells with immunoregulatory capacity that are present in most adult organs. We previously demonstrated that co-culture of C57BL/6 kidney-derived MSCs (KSCs) in syngeneic bone marrow-derived dendritic cell (DC) culture induced a DC phenotype (KSC-DC) with reduced major histocompatibility complex (MHC) class II/increased CD80 expression and ability to suppress T-cell responses. METHODS: To study their effects on allogeneic DCs, C57BL/6 KSCs were added to incipient BALB/c DC culture, with surface expression of MHC class II/CD80 measured by fluorescence-activated cell sorting. The ability to stimulate T-cell responses was then assessed in an allogeneic mixed leukocyte response. Next, we isolated either BALB/c (donor) or C57BL/6 (recipient) KSC-DCs from co-culture and measured the tempo of rejection after cotransplantation with islet grafts in a mouse model of islet transplantation. Finally, we measured the effects of KSC-DC stimulation on B-cell proliferation and IgM/IgG production in allogeneic cultures. RESULTS: C57BL/6 KSCs induced a BALB/c DC phenotype with significantly decreased MHC class II, increased CD80 expression, and decreased T-cell stimulatory capacity in the mixed leukocyte response (P<0.01 vs. control). Cotransplantation of donor (BALB/c) but not recipient (C57BL/6) KSC-DCs resulted in significant delay of rejection after islet transplantation (P<0.01 vs. control). Finally, stimulation by KSC-DCs resulted in significantly reduced B-cell proliferation and antibody production in allogeneic culture (P<0.01 vs. control). CONCLUSIONS: Our results highlight an important mechanism of MSC-based immunotherapy and its potential for use in clinical transplantation as prevention of rejection and possibly sensitization.
Assuntos
Rejeição de Enxerto/imunologia , Células-Tronco Mesenquimais/imunologia , Transplante Isogênico/imunologia , Animais , Formação de Anticorpos , Linfócitos B/imunologia , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Células da Medula Óssea/imunologia , Técnicas de Cultura de Células , Células Dendríticas/citologia , Células Dendríticas/imunologia , Citometria de Fluxo/métodos , Rejeição de Enxerto/prevenção & controle , Antígenos de Histocompatibilidade Classe II/imunologia , Transplante das Ilhotas Pancreáticas/imunologia , Ativação Linfocitária , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transplante Homólogo/imunologiaRESUMO
Kidney ischemia/reperfusion injury (IRI) is a common and serious problem in hospitalized patients. Immune cell trafficking and leukocyte-endothelial adhesion potentiate kidney IRI. An important immunomodulatory role of T lymphocytes has been elucidated in IRI. Regulatory T cells are a lymphocyte subset that has recently been demonstrated to perform a protective role both in early injury from IRI as well as in later repair. The immune system also participates in distant organ effects during kidney IRI. Studies focusing on immune aspects of kidney IRI have enabled the discovery of promising novel therapeutic and diagnostic approaches.
Assuntos
Pesquisa Biomédica , Rim/lesões , Traumatismo por Reperfusão/imunologia , Linfócitos T Reguladores/imunologia , Alergia e Imunologia , Animais , Baltimore , Humanos , Rim/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/metabolismo , UniversidadesRESUMO
BACKGROUND: BK virus nephropathy (BKVN) is a significant cause of renal allograft loss. Although overall intensity of immunosuppression is the greatest risk factor, recipient immune factors likely also play a role in the pathogenesis. Dendritic cells (DC) are potent antigen-presenting cells important for the induction of anti-viral cytotoxic T-cell responses. In a previous univariate analysis, we demonstrated a peripheral blood DC (PBDC) deficiency in patients with biopsy-proven BKVN, raising the possibility that reduction in DC predisposed to BK reactivation. METHODS: In this study, we refined our previous analysis by comparing random posttransplant PBDC levels between an expanded group of patients with BKVN and controls without viremia using a multivariate analysis that accounted for factors known to influence PBDC levels. Next, we compared pretransplant PBDC levels between patients stratified by the presence or absence of posttransplant viremia. Finally, we assessed the predictive value of pretransplant PBDC levels for the development of posttransplant viremia. RESULTS: Analyses revealed a PBDC level deficiency not only posttransplant in patients with BKVN but also pretransplant in patients who subsequently developed posttransplant BK viremia. Furthermore, we identified a pretransplant PBDC level that is a reasonable predictor for the development of posttransplant viremia. CONCLUSIONS: Our results identify PBDC deficiency as a previously unrecognized risk factor for BKV reactivation after renal transplantation. Pretransplant PBDC monitoring may prove to be a useful clinical tool in the assessment of patient vulnerability to BKVN posttransplant, which may allow more focused screening.
Assuntos
Vírus BK , Células Dendríticas/imunologia , Transplante de Rim/imunologia , Infecções por Polyomavirus/epidemiologia , Infecções Tumorais por Vírus/epidemiologia , Viremia/imunologia , Adulto , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/virologia , Vírus BK/genética , Biópsia , Linfócitos T CD8-Positivos/imunologia , Primers do DNA , DNA Viral/genética , DNA Viral/isolamento & purificação , Células Dendríticas/virologia , Citometria de Fluxo , Amplificação de Genes , Humanos , Consentimento Livre e Esclarecido , Interleucina-2/biossíntese , Interleucina-2/sangue , Transplante de Rim/efeitos adversos , Transplante de Rim/patologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Lipopolissacarídeos/farmacologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/patologia , Linfócitos T Citotóxicos/imunologia , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/patologia , Viremia/epidemiologia , Viremia/patologiaRESUMO
Mouse antithymocyte globulin (mATG) prevents, as well as reverses, type 1 diabetes in NOD mice, through mechanisms involving modulation of the immunoregulatory activities of T lymphocytes. Dendritic cells (DC) play a pivotal role in the generation of T cell responses, including those relevant to the autoreactive T cells enabling type 1 diabetes. As Abs against DC are likely generated during production of mATG, we examined the impact of this preparation on the phenotype and function of DC to elucidate novel mechanisms underlying its beneficial activities. In vivo, mATG treatment transiently induced the trafficking of mature CD8(-) predominant DC into the pancreatic lymph node of NOD mice. Splenic DC from mATG-treated mice also exhibited a more mature phenotype characterized by reduced CD8 expression and increased IL-10 production. The resultant DC possessed a potent capacity to induce Th2 responses when cultured ex vivo with diabetogenic CD4(+) T cells obtained from BDC2.5 TCR transgenic mice. Cotransfer of these Th2-deviated CD4(+) T cells with splenic cells from newly diabetic NOD mice into NOD.RAG(-/-) mice significantly delayed the onset of diabetes. These studies suggest the alteration of DC profile and function by mATG may skew the Th1/Th2 balance in vivo and through such actions, represent an additional novel mechanism by which this agent provides its beneficial activities.
Assuntos
Soro Antilinfocitário/administração & dosagem , Soro Antilinfocitário/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Diabetes Mellitus/imunologia , Animais , Soro Antilinfocitário/farmacologia , Medula Óssea/imunologia , Diferenciação Celular/imunologia , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Feminino , Interleucina-10/biossíntese , Interleucina-10/imunologia , Camundongos , Camundongos Endogâmicos NOD , Coelhos , Baço/imunologia , Células Th2/imunologiaRESUMO
Multipotent mesenchymal stromal cells from the bone marrow ameliorate acute kidney injury through a mechanism other than transdifferentiation into renal tissue. Stromal cells exert immunoregulatory effects on dendritic and T cells, both of which are important in the pathophysiology of immune-mediated kidney injury. We hypothesized that similar cells with immunoregulatory function exist within the adult kidney. We isolated murine kidney-derived cells with morphologic features, growth properties, and an immunophenotype characteristic of mesenchymal stromal cells. These cells lacked lineage markers and could be differentiated into mesodermal cell lineages, including osteocytes and adipocytes. Furthermore, these kidney-derived cells induced the generation of bone marrow-derived dendritic cells with significantly reduced MHC II expression, increased CD80 expression, increased IL-10 production and the inability to stimulate CD4+ T cell proliferation in allogeneic and nominal antigen-specific cultures. Experiments in mixed and transwell cultures demonstrated that the production of soluble immune modulators, such as IL-6, was responsible for these effects on dendritic cell differentiation and maturation. Contact-dependent mechanisms, however, inhibited mitogenic T cell proliferation. In summary, kidney-derived cells may suppress inflammation in the kidney in vivo; a better understanding of their biology could have therapeutic implications in a wide variety of immune-mediated kidney diseases.