IL-1α Mediated Chorioamnionitis Induces Depletion of FoxP3+ Cells and Ileal Inflammation in the Ovine Fetal Gut

Endotoxin induced chorioamnionitis increases IL-1 and provokes an inflammatory response in the fetal ileum that interferes with intestinal maturation. In the present study, we tested in an ovine chorioamnionitis model whether IL-1 is a major cytokine driving the inflammatory response in the fetal ileum.Sheep bearing singleton fetuses received a single intraamniotic injection of recombinant ovine IL-1α at 7, 3 or 1 d before caesarian delivery at 125 days gestational age (term = 150 days).3 and 7 d after IL-1α administration, intestinal mRNA levels for IL-4, IL-10, IFN-γ and TNF-α were strongly elevated. Numbers of CD3+ and CD4+ T-lymphocytes and myeloidperoxidase+ cells were increased whereas FoxP3+ T-cells were detected at low frequency. This increased proinflammatory state was associated with ileal mucosal barrier loss as demonstrated by decreased levels of the intestinal fatty acid binding protein and disruption of the tight junctional protein ZO-1.Intraamniotic IL-1α causes an acute detrimental inflammatory response in the ileum, suggesting that induction of IL-1 is a critical element in the pathophysiological effects of endotoxin induced chorioamnionitis. A disturbed balance between T-effector and FoxP3+ cells may contribute to this process

PIRCHE-II is related to graft failure after kidney transplantation

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor-recipient couples that were transplanted between 1995 and 2005. For these donors-recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04-1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10-1.34, p < 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival

PIRCHE-II Is Related to Graft Failure after Kidney Transplantation

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor–recipient couples that were transplanted between 1995 and 2005. For these donors–recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04–1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10–1.34, p &lt; 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival

T-Cell Epitopes Shared Between Immunizing HLA and Donor HLA Associate With Graft Failure After Kidney Transplantation

CD4(+) T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4(+) memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4(+) memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4(+) memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the donor HLA were estimated and the number of shared PIRCHE-II epitopes was calculated. We show that the natural logarithm-transformed PIRCHE-II overlap score, or Shared T-cell EPitopes (STEP) score, significantly associates with the 10-year risk of death-censored kidney graft failure, suggesting that the presence of pre-transplant donor-reactive CD4(+) memory T-helper cells might be a strong indicator for the risk of graft failure following kidney transplantation

Optimizing outcomes of patients with systemic sclerosis

Despite improved health care standards and better understanding of pathophysiology, systemic sclerosis (SSc) has an increased mortality and high morbidity. Management of SSc can be challenging due to its heterogeneous nature, multi-organ involvement and limited therapeutic options. This thesis zooms in on organisation of health care and autologous stem cell transplantation (SCT) as potential targets to improve outcomes. The organization of Dutch SSc care was investigated and evaluated from different perspectives. Ways to improve quality of care were explored. Our large cross-sectional study including 650 Dutch SSc patients from thirteen hospitals, showed that patients are generally satisfied with their care. Most important points for improvement from the patient' perspective were education, clear and transparant definitions of SSc expert centers accesible for patients, and collaboration between doctors. Also, patients prioritized good patient-doctor interaction and structural multidisciplinary collaboration as the most relevant quality indicators for SSc care. In addition to the perspective of patients on health care organization, recommendations were formulated in a multidisciplinary study among doctors, nurses and paramedics. Five domains in need for improvement (shared care and multidisciplinary collaboration, exchange of medical data, education, patient empowerment and non-pharmacological care) were identified and discussed in this meeting. Furthermore, in order to support collaboration and referral structures on a regional and national level, a Delphi consensus study was done, resulting in requirements for two types of SSc centres with different levels of expertise. Another neglected area in SSc care is the perspective of caregivers. In an exploratory study the impact of SSc on caregivers and their unmet needs are described. Caregivers reported that their relationship, social lives and emotional wellbeing were affected by the disease of their loved-one. Moreover, supporting their partner or friend was sometimes hindered by a lack of knowledge about the disease, insight in the overall treatment strategy and skills to optimise communication. The importance of support and information for patients, also provided by health care professionals and peers was emphasized in this thesis. This is particularly true in the context of a complex treatment modality such as SCT. SCT is increasingly used in severe form of SSc. This treatment has demonstrated to greatly improve long-term outcomes in the diffuse subset of SSc. However, treatment-related mortality is relatively high. In the absence of strong evidence on the exact place of SCT in the course of the disease, treatment decision-making rests on the shoulders of patients and their doctors. Patient reported that this process can be very difficult and strongly guided by the physician. Also, a study on the experiences of patients during and after SCT showed that this therapy has a major physical and psychosocial impact, and that post-treatment counseling should be offered pro-actively. Lastly, in order to optimise outcomes, more research is needed to determine the optimal treatment strategy. The international UPSIDE study aims to provide more insight in optimal timing and patient selection with regard to SCT and immunosuppressive therapy. The study design is described in this thesis

Optimizing outcomes of patients with systemic sclerosis

Despite improved health care standards and better understanding of pathophysiology, systemic sclerosis (SSc) has an increased mortality and high morbidity. Management of SSc can be challenging due to its heterogeneous nature, multi-organ involvement and limited therapeutic options. This thesis zooms in on organisation of health care and autologous stem cell transplantation (SCT) as potential targets to improve outcomes. The organization of Dutch SSc care was investigated and evaluated from different perspectives. Ways to improve quality of care were explored. Our large cross-sectional study including 650 Dutch SSc patients from thirteen hospitals, showed that patients are generally satisfied with their care. Most important points for improvement from the patient' perspective were education, clear and transparant definitions of SSc expert centers accesible for patients, and collaboration between doctors. Also, patients prioritized good patient-doctor interaction and structural multidisciplinary collaboration as the most relevant quality indicators for SSc care. In addition to the perspective of patients on health care organization, recommendations were formulated in a multidisciplinary study among doctors, nurses and paramedics. Five domains in need for improvement (shared care and multidisciplinary collaboration, exchange of medical data, education, patient empowerment and non-pharmacological care) were identified and discussed in this meeting. Furthermore, in order to support collaboration and referral structures on a regional and national level, a Delphi consensus study was done, resulting in requirements for two types of SSc centres with different levels of expertise. Another neglected area in SSc care is the perspective of caregivers. In an exploratory study the impact of SSc on caregivers and their unmet needs are described. Caregivers reported that their relationship, social lives and emotional wellbeing were affected by the disease of their loved-one. Moreover, supporting their partner or friend was sometimes hindered by a lack of knowledge about the disease, insight in the overall treatment strategy and skills to optimise communication. The importance of support and information for patients, also provided by health care professionals and peers was emphasized in this thesis. This is particularly true in the context of a complex treatment modality such as SCT. SCT is increasingly used in severe form of SSc. This treatment has demonstrated to greatly improve long-term outcomes in the diffuse subset of SSc. However, treatment-related mortality is relatively high. In the absence of strong evidence on the exact place of SCT in the course of the disease, treatment decision-making rests on the shoulders of patients and their doctors. Patient reported that this process can be very difficult and strongly guided by the physician. Also, a study on the experiences of patients during and after SCT showed that this therapy has a major physical and psychosocial impact, and that post-treatment counseling should be offered pro-actively. Lastly, in order to optimise outcomes, more research is needed to determine the optimal treatment strategy. The international UPSIDE study aims to provide more insight in optimal timing and patient selection with regard to SCT and immunosuppressive therapy. The study design is described in this thesis

Heat shock proteins and their immunomodulatory role in inflammatory arthritis

Autoimmune diseases, including inflammatory arthritis, are characterized by a loss of self-tolerance, leading to an excessive immune responses and subsequent ongoing inflammation. Current therapies are focused on dampening this inflammation, but a permanent state of tolerance is seldom achieved. Therefore, novel therapies that restore and maintain tolerance are needed. Tregs could be a potential target to achieve permanent immunotolerance. Activation of Tregs can be accomplished when they recognize and bind their specific antigens. HSPs are proteins present in all cells and are upregulated during inflammation. These proteins are immunogenic and can be recognized by Tregs. Several studies in animal models and in human clinical trials have shown the immunoregulatory effects of HSPs and their protective effects in inflammatory arthritis. In this review, an overview is presented of the immunomodulatory effects of several members of the HSP family in general and in inflammatory arthritis. These effects can be attributed to the activation of Tregs through cellular interactions within the immune system. The effect of HSP-specific therapies in patients with inflammatory arthritis should be explored further, especially with regard to long-term efficacy and safety and their use in combination with current therapeutic approaches