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Clinical trials are currently testing whether induction of haploidentical mixed chimerism (Haplo-MC) induces organ transplantation tolerance. Whether Haplo-MC can be used to treat established autoimmune diseases remains unknown. Here, we show that established autoimmunity in euthymic and adult-thymectomized NOD (H-2g7) mice was cured by induction of Haplo-MC under a non-myeloablative anti-thymocyte globulin-based conditioning regimen and infusion of CD4+ T cell-depleted hematopoietic graft from H-2b/g7 F1 donors that expressed autoimmune-resistant H-2b or from H-2s/g7 F1 donors that expressed autoimmune-susceptible H-2s. The cure was associated with enhanced thymic negative selection, increased thymic Treg (tTreg) production, and anergy or exhaustion of residual host-type autoreactive T cells in the periphery. The peripheral tolerance was accompanied by expansion of donor- and host-type CD62L-Helios+ tTregs as well as host-type Helios-Nrp1+ peripheral Tregs (pTregs) and PD-L1hi plasmacytoid DCs (pDCs). Depletion of donor- or host-type Tregs led to reduction of host-type PD-L1hi pDCs and recurrence of autoimmunity, whereas PD-L1 deficiency in host-type DCs led to reduction of host-type pDCs and Helios-Nrp1+ pTregs. Thus, induction of Haplo-MC reestablished both central and peripheral tolerance through mechanisms that depend on allo-MHC+ donor-type DCs, PD-L1hi host-type DCs, and the generation and persistence of donor- and host-type tTregs and pTregs. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment in survivors of blood or bone marrow transplantation (BMT) is well documented. However, to the authors' knowledge, the clinical relevance of self-endorsed cognitive problems and their relation to objectively assessed cognitive impairment is not known.Methods: The authors assessed cognitive impairment in 378 BMT recipients (median age, 52.2 years, 40% of whom were female and 68% of whom were non-Hispanic white) and 98 healthy controls at 5 predetermined time points: at baseline (before BMT) and at 6 months, 1 year, 2 years, and 3 years after BMT. Self-endorsed cognitive problems were evaluated using the Neuropsychological Impairment Scale (NIS) and correlated with a standardized 2-hour battery of objective cognitive testing at each time point. The authors examined the magnitude of difference in self-endorsed cognitive problems between BMT recipients and healthy controls, and the rate of change in scores over time. Multivariable analyses were used to identify clinical and/or demographic variables associated with self-endorsed cognitive problems. The authors also examined the association between cognitive impairment and returning to work after BMT.Results: Compared with healthy controls, BMT recipients endorsed more cognitive problems (P < .001) at all time points, and the rate of change in NIS scores was found to be significantly greater in BMT recipients. Fatigue was associated with greater endorsement of cognitive problems at 1 year after BMT (odds ratio, 4.23; 95% CI, 2.1-8.3 [P < .001]). Overall, there was a statistically significant, modest correlation noted between self-endorsed cognitive problems and objective cognitive impairment (range, 0.401-0.445 [P ≤ .01]). Higher self-endorsed cognitive problems were associated with a 3.7-fold (P = .02) higher odds of not returning to work at 3 years after BMT.Conclusions: The results of the current study demonstrated that self-endorsed cognitive problems can help to identify vulnerable patient subpopulations for detailed cognitive assessment and possible cognitive remediation. [ABSTRACT FROM AUTHOR]

Background: Patients with non-Hodgkin lymphoma (NHL) have an increased risk of venous thromboembolism (VTE), particularly when they are receiving treatment. Blood or marrow transplantation (BMT) is recommended for relapsed/refractory NHL, and the risk of VTE after these patients undergo BMT is uncertain.Methods: Patients with NHL who survived 2 years or longer after BMT were surveyed for long-term health outcomes, including VTE. The median follow-up was 8.1 years (interquartile range, 5.6-12.9 years). The risk of VTE in 734 patients with NHL versus 897 siblings without a history of cancer and the risk factors associated with VTE were analyzed.Results: BMT survivors of NHL were at increased risk for VTE in comparison with siblings (odds ratio for allogeneic BMT survivors, 4.61; P < .0001; odds ratio for autologous BMT survivors, 1.75; P = .035). The cumulative incidence of VTE was 6.3% ± 0.9% at 5 years after BMT and 8.1% ± 1.1% at 10 years after BMT. In allogeneic BMT recipients, an increased body mass index (BMI; hazard ratio [HR] for BMI of 25-30 kg/m2 , 3.52; 95% confidence interval [CI], 1.43-8.64; P = .006; HR for BMI > 30 kg/m2 , 3.44; 95% CI, 1.15-10.23; P = .027) and a history of chronic graft-versus-host disease (HR, 3.33; 95% CI, 1.59-6.97; P = .001) were associated with an increased risk of VTE. Among autologous BMT recipients, a diagnosis of coronary artery disease (HR, 5.94; 95% CI, 1.7-20.71; P = .005) and prior treatment with carmustine (HR, 4.91; 95% CI, 1.66-14.51; P = .004) were associated with increased VTE risk.Conclusions: Patients with NHL who survive BMT are at risk for developing late occurring VTE, and ongoing vigilance for this complication is required. Future studies assessing the role of thromboprophylaxis in high-risk patients with NHL are needed. [ABSTRACT FROM AUTHOR]