RESUMEN
Rejection remains a major cause of renal allograft failure. Current diagnostic studies, interrogating the blood or urine, lack the sensitivity and specificity for early detection of rejection. Transplant kidney biopsy remains the gold standard, but is associated with morbidity. Advances in understanding the immunobiology of rejection have led to multiple, novel diagnostic tests facilitating non-invasive, earlier detection of renal allograft rejection.
Asunto(s)
Trasplante de Riñón , Insuficiencia Renal , Biomarcadores , Rechazo de Injerto/diagnóstico , Humanos , RiñónRESUMEN
BACKGROUND: Developing a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells' proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection. METHODS: Using 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets. RESULTS: An exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature's negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell-mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature's negative predictive value was 90.6% and its positive predictive value was 77.8%. CONCLUSIONS: Our findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.
RESUMEN
Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. Current immunosuppression protocols are not designed to target antigen-specific alloimmunity and are uncapable of preventing chronic allograft injury. As myeloid-derived suppressor cells (MDSCs) are potent immunoregulatory cells, we tested whether donor-derived MDSCs can protect heart transplant allografts in an antigen-specific manner. C57BL/6 (H2Kb, I-Ab) recipients pre-treated with BALB/c MDSCs were transplanted with either donor-type (BALB/c, H2Kd, I-Ad) or third-party (C3H, H2Kk, I-Ak) cardiac grafts. Spleens and allografts from C57BL/6 recipients were harvested for immune phenotyping, transcriptomic profiling and functional assays. Single injection of donor-derived MDSCs significantly prolonged the fully MHC mismatched allogeneic cardiac graft survival in a donor-specific fashion. Transcriptomic analysis of allografts harvested from donor-derived MDSCs treated recipients showed down-regulated proinflammatory cytokines. Immune phenotyping showed that the donor MDSCs administration suppressed effector T cells in recipients. Interestingly, significant increase in recipient endogenous CD11b+Gr1+ MDSC population was observed in the group treated with donor-derived MDSCs compared to the control groups. Depletion of this endogenous MDSCs with anti-Gr1 antibody reversed donor MDSCs-mediated allograft protection. Furthermore, we observed that the allogeneic mixed lymphocytes reaction was suppressed in the presence of CD11b+Gr1+ MDSCs in a donor-specific manner. Donor-derived MDSCs prolong cardiac allograft survival in a donor-specific manner via induction of recipient's endogenous MDSCs.
Asunto(s)
Supervivencia de Injerto/inmunología , Trasplante de Corazón/métodos , Células Supresoras de Origen Mieloide/inmunología , Aloinjertos/inmunología , Animales , Rechazo de Injerto/inmunología , Rechazo de Injerto/mortalidad , Trasplante de Corazón/mortalidad , Trasplante de Células Madre Hematopoyéticas , Tolerancia Inmunológica , Terapia de Inmunosupresión/métodos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Células Mieloides/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/fisiología , Linfocitos T/inmunología , Donantes de Tejidos , Trasplante HomólogoRESUMEN
Successful engraftment of organ transplants has traditionally relied on preventing the activation of recipient (host) T cells. Once T-cell activation has occurred, however, stalling the rejection process becomes increasingly difficult, leading to graft failure. Here we demonstrate that graft-infiltrating, recipient (host) dendritic cells (DCs) play a key role in driving the rejection of transplanted organs by activated (effector) T cells. We show that donor DCs that accompany heart or kidney grafts are rapidly replaced by recipient DCs. The DCs originate from non-classical monocytes and form stable, cognate interactions with effector T cells in the graft. Eliminating recipient DCs reduces the proliferation and survival of graft-infiltrating T cells and abrogates ongoing rejection or rejection mediated by transferred effector T cells. Therefore, host DCs that infiltrate transplanted organs sustain the alloimmune response after T-cell activation has already occurred. Targeting these cells provides a means for preventing or treating rejection.
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Células Dendríticas/inmunología , Rechazo de Injerto/inmunología , Linfocitos T/inmunología , Animales , Trasplante de Corazón , Trasplante de Riñón , Activación de Linfocitos , Ratones , TrasplantesRESUMEN
Bony fish are among the first vertebrates to possess an innate and adaptive immune system. In these species, the kidney has a dual function: filtering solutes similar to mammals and acting as a lymphoid organ responsible for hematopoiesis and antigen processing. Recent studies have shown that the mammalian kidney has an extensive network of mononuclear phagocytes, whose function is not fully understood. Here, we employed two-photon intravital microscopy of fluorescent reporter mice to demonstrate that renal dendritic cells encase the microvasculature in the cortex, extend dendrites into the peritubular capillaries, and sample the blood for antigen. We utilized a mouse model of systemic bacterial infection as well as immune complexes to demonstrate antigen uptake by renal dendritic cells. As a consequence, renal dendritic cells mediated T-cell migration into the kidney in an antigen-dependent manner in the setting of bacterial infection. Thus, renal dendritic cells may be uniquely positioned to play an important role not only in surveillance of systemic infection but also in local infection and autoimmunity.
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Autoinmunidad , Infecciones Bacterianas/inmunología , Movimiento Celular/inmunología , Células Dendríticas/inmunología , Riñón/inmunología , Linfocitos T/fisiología , Animales , Presentación de Antígeno/inmunología , Complejo Antígeno-Anticuerpo , Células Dendríticas/ultraestructura , Microscopía Intravital , Riñón/irrigación sanguínea , Riñón/citología , Riñón/ultraestructura , Ratones , Ratones Endogámicos C57BL , Microscopía de Fluorescencia por Excitación Multifotónica , Modelos AnimalesRESUMEN
Pancreatic islet transplantation is a promising therapy for diabetes, but acute rejection of the islets by host effector T cells has hindered clinical application. In this study, we addressed the mechanisms of CD8(+) effector T cell migration to islet grafts because interrupting this step is key to preventing rejection. We found that effector T cell migration to revascularized islet transplants in mice is dependent on non-self Ag recognition rather than signaling via Gαi-coupled chemokine receptors. Presentation of non-self Ag by donor cells was necessary for migration, whereas Ag presentation by recipient cells was dispensable. We also observed that deficiency of SKAP1, an immune cell adaptor downstream of the TCR and important for integrin activation, prolongs allograft survival but does not reduce effector T cell migration to the graft. Therefore, effector T cell migration to transplanted islets is Ag driven, not chemokine driven, but SKAP1 does not play a critical role in this process.
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Presentación de Antígeno/inmunología , Linfocitos T CD8-positivos/inmunología , Quimiotaxis de Leucocito/inmunología , Rechazo de Injerto/inmunología , Trasplante de Islotes Pancreáticos/inmunología , Animales , Islotes Pancreáticos/inmunología , Ratones , Modelos AnimalesRESUMEN
This review serves as an introduction to an Immunology Series for the Nephrologist published in CJASN. It provides a brief overview of the immune system, how it works, and why it matters to kidneys. This review describes in broad terms the main divisions of the immune system (innate and adaptive), their cellular and tissue components, and the ways by which they function and are regulated. The story is told through the prism of evolution in order to relay to the reader why the immune system does what it does and why imperfections in the system can lead to renal disease. Detailed descriptions of cell types, molecules, and other immunologic curiosities are avoided as much as possible in an effort to not detract from the importance of the broader concepts that define the immune system and its relationship to the kidney.