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Objective: Thrombocytopenia is a common complication of hematopoietic stem-cell transplantation (HSCT), though many patients will become immune refractory to platelet transfusions over time. We built and evaluated an electronic health record (EHR)-integrated, standards-based application that enables blood-bank clinicians to match platelet inventory with patients using data previously not available at the point-of-care, like human leukocyte antigen (HLA) data for donors and recipients. Materials and methods: The web-based application launches as an EHR-embedded application or as a standalone application. The application coalesces disparate data streams into a unified view, including platelet count, HLA data, demographics, and real-time inventory. We looked at application usage over time and developed a multivariable logistic regression model to compute odds ratios that a patient undergoing HSCT would have a complicated thrombocytopenia course, with several model covariates including pre-/post-application deployment. Results: Usage of the application has been consistent since launch, with a slight dip during the first COVID wave. Our model, which included 376 patients in the final analysis, did not demonstrate a significantly decreased odds that a patient would have a complicated thrombocytopenia course after application deployment as compared to before application deployment. Discussion: We built an EHR-integrated application to improve platelet transfusion processes. Whereas our model did not demonstrate decreased odds of a patient having a complicated thrombocytopenia course, there are other workflow and clinical benefits that will benefit from future evaluation. Conclusion: A web-based, EHR-integrated application was built and integrated into our EHR system and is now part of the standard operating procedures of our blood bank.

Hyperoxaluria is an important and underrecognized cause for allograft dysfunction and loss after transplantation. It is potentially treatable if recognized in a timely fashion. Research is ongoing to expand the array of therapeutic options available to treat this. We present a case of a 59-year-old gentleman who underwent deceased donor renal transplantation that was complicated by delayed graft function necessitating continuation of renal replacement therapy. His initial biopsy showed extensive acute tubular necrosis with associated peritubular capillaritis and interstitial nephritis and oxalate crystals in several tubules. Despite receiving methylprednisolone to treat moderate acute cellular rejection, he remained dialysis dependent with minimal urine output. An interval renal allograft biopsy revealed residual acute tubular necrosis with extensive oxalate crystals now visible in many tubules. His plasma oxalate level was concurrently elevated to 19.3 μmol/L (reference range ≤ 1.9 μmol/L). He commenced calcium citrate to manage his hyperoxaluria and ultimately became dialysis independent at 3 weeks after transplantation. This case provides an important example of accelerated oxalate nephropathy as an underappreciated contributor to delayed graft function after renal transplantation. Our accompanying discussion provides an update on current therapeutic measures for managing this challenging condition.

Background: A number of studies have demonstrated the role of CX3CR1 in regulating the migration of monocytes into peripheral tissue and their transformation into DC. No data are yet available on the importance of chemokine pathways in regulating homeostasis of dendritic cell (DC) in heart transplants. Recently, we showed that recipients of heart allografts from CXC3R1-/- donors show longer survival. To dissect the role of CX3CR1 signaling in the homeostasis of heart dDC, we have developed and tested a novel in vivo imaging tool in CX3CR1GFP/+ DC (B6 background) heart graft into BALB/c recipient model.Results: Majority of GFP positive cells located in the middle of cardiac myocyte and their shapes were stretching and still roundish in the early phase of post transplant (3 and 24hours). However, images from 72hours at cardiac graft showed many of GFP positive cells move to vessel areas. In addition, significant immunological events such as GFP positive cell exiting from cardiac myocyte and changes of GFP positive cell motility and shape were detected. GFP positive cells were detected in the vasculature and lymph nodes. Only 1 GFP positive cell was observed in three lymph nodes (2 mesenteric, 1 inguinal) (72hours). Conclusions: Current data will define the function of dDC in regulating alloimmune responses in vivo and provide information to develop novel strategies designed to achieve durable tolerance and prevent chronic rejection.

Background: We have previously found that CD4+CD25+ regulatory T cells (T regs) can adoptively transfer tolerance after its induction with co-stimulatory blockade in a mouse model of murine cardiac allograft transplantation. In these experiments, we tested an hypothesis with three components: 1) the T regs that transfer tolerance have the capacity for linked suppression, 2) the determinants that stimulate the T regs are expressed by the indirect pathway, and 3) the donor peptides contributing to these indirect determinants are derived from donor MHC antigens. Methods: 1st heart transplants were performed from the indicated donor strain to B10.D2 recipients along with co-stimulatory blockade treatment (250μg i.p. injection of MR1 on day 0 and 250μg i.p. injection of CTLA-4 Ig on day 2). At least 8 weeks later a 2nd heart transplant was performed to a new B10.D2 recipient that had been irradiated with 450 cGy. This recipient was given 40 x 106 naïve B10.D2 spleen cells plus 40 x 106 B10.D2 spleen cells from the first (tolerant) recipient. We performed 3 different types of heart transplants with using various donor.Results: 1. T regs suppress the graft rejection in an antigen-specific manner. 2. T regs generated in the face of MHC disparities suppress the rejection of grafts expressing third party MHC along with tolerant MHC. Conclusion:The limits of linkage appear to be quantitative and not universally determined by either the indirect pathway or by peptides of donor MHC antigens.

Background: Calculated panel reactive antibody (cPRA) scoring is used to assess whether platelet refractoriness is mediated by human leukocyte antigen (HLA) antibodies in the recipient. cPRA testing uses a national sample of US kidney donors to estimate the population frequency of HLA antigens, which may be different than HLA frequencies within local platelet inventories. We aimed to determine the impact on patient cPRA scores of using HLA frequencies derived from typing local platelet donations rather than national HLA frequencies. Methods: We built an open-source web service to calculate cPRA scores based on national frequencies or custom-derived frequencies. We calculated cPRA scores for every hematopoietic stem cell transplantation (HSCT) patient at our institution based on the United Network for Organ Sharing (UNOS) frequencies and local frequencies. We compared frequencies and correlations between the calculators, segmented by gender. Finally, we put all scores into three buckets (mild, moderate, and high sensitizations) and looked at intergroup movement. Results: 2531 patients that underwent HSCT at our institution had at least 1 antibody and were included in the analysis. Overall, the difference in medians between each group's UNOS cPRA and local cPRA was statistically significant, but highly correlated (UNOS vs. local total: 0.249 and 0.243, ρ = 0.994; UNOS vs. local female: 0.474 and 0.463, ρ = 0.987, UNOS vs. local male: 0.165 and 0.141, ρ = 0.996;P< 0.001 for all comparisons). The median difference between UNOS and cPRA scores for all patients was low (male: 0.014, interquartile range [IQR]: 0.004–0.029; female: 0.0013, IQR: 0.003–0.028). Placement of patients into three groups revealed little intergroup movement, with 2.96% (75/2531) of patients differentially classified. Conclusions: cPRA scores using local frequencies were modestly but significantly different than those obtained using national HLA frequencies. We released our software as open source, so other groups can calculate cPRA scores from national or custom-derived frequencies. Further investigation is needed to determine whether a local-HLA frequency approach can improve outcomes in patients who are immune-refractory to platelets.

Despite significant nephrotoxicity, calcineurin inhibitors (CNIs) remain the cornerstone of immunosuppression in solid organ transplantation. We, along with others, have reported tolerogenic properties of anti-thymocyte globulin (ATG, Thymoglobulin®), evinced by its ability both to spare Tregs from depletion in vivo and, when administered at low, non-depleting doses, to expand Tregs ex vivo. Clinical trials investigating B7/CD28 blockade (LEA29Y, Belatacept) in kidney transplant recipients have proven that the replacement of toxic CNI use is feasible in selected populations.Rabbit polyclonal anti-murine thymocyte globulin (mATG) was administered as induction and/or prolonged, low-dose therapy, in combination with CTLA4-Ig, in a stringent, fully MHC-mismatched murine skin transplant model to assess graft survival and mechanisms of action.Prolonged, low-dose mATG, combined with CTLA4-Ig, effectively promotes engraftment in a stringent transplant model. Our data demonstrate that mATG achieves graft acceptance primarily by promoting Tregs, while CTLA4-Ig enhances mATG function by limiting activation of the effector T cell pool in the early stages of treatment, and by inhibiting production of anti-rabbit antibodies in the maintenance phase, thereby promoting regulation of alloreactivity.These data provide the rationale for development of novel, CNI-free clinical protocols in human transplant recipients.