Role of the Thymus in Transplantation Tolerance in Miniature Swine. I. Requirement of the Thymus for Rapid and Stable Induction of Tolerance to Class I–mismatched Renal Allografts

The almost uniform failure in transplant patients of tolerance-inducing regimens that have been found to be effective in rodents, has made it necessary to examine large animal models before testing of new approaches clinically. Miniature swine have been shown to share many relevant immunologic parameters with humans, and because of their reproducible genetics, have proved extremely useful in providing such a large animal model. We have previously shown that indefinite systemic tolerance to renal allografts in miniature swine is induced in 100% of cases across a two-haplotype class I plus minor histocompatibility antigen disparity by a 12-d course of Cyclosporine A (CyA), in contrast to irreversible rejection observed uniformly without CyA treatment. In the present study, we have examined the role of the thymus during the induction of tolerance by performing a complete thymectomy 21 d before renal transplantation. This analysis demonstrated a striking difference between thymectomized and nonthymectomized animals. Thymectomized swine developed acute cellular rejection characterized by a T cell (CD25+) infiltrate, tubulitis, endothelialitis and glomerulitis, and anti–donor CTL reactivity in vitro. Nonthymectomized and sham thymectomized animals had a mild T cell infiltrate with few CD25+ cells and no anti–donor CTL response in vitro. These results indicate that the thymus is required for rapid and stable induction of tolerance

Systematic pathological component scores for skin-containing vascularized composite allografts

Clinical management of skin-containing vascularized composite allografts (VCA) requires accurate assessment of the graft status, typically based on skin biopsies. The Banff 2007 Working Classification proposed 4 grades of acute rejection, but did not score individual features or include vascular rejection. Here we report a systematic scoring system developed from MHC-mismatched porcine skin-containing VCA. Biopsies from 20 VCA, 9 autologous skin flaps and 9 normal skin were analyzed to optimize the methodology and set thresholds. The components quantified were: perivascular cells/dermal vessel (pc), perivascular dermal infiltrate area (pa), luminal leukocytes/capillary or venule (c), epidermal infiltrate (ei), epidermal apoptosis or necrosis (e), endarteritis (v), and chronic allograft vasculopathy (cav). To evaluate prognostic value, we scored a separate group of 28 serial biopsies from 8 recipients (4 that were ultimately accepted and 4 that rejected. Parameters on the initial biopsies predicting later graft rejection included pc (p < 0.02), pa (p < 0.03), ei (p < 0.0005), e (p < 0.003) and c (p < 0.005). Reproducibility between 2 pathologists blinded to clinical data was acceptable, with weighted kappa scores for pc (0.673), pa (0.399), ei (0.464), e (0.663), v (0.766), and c (0.642). This component scoring system can be adapted clinically, since human and porcine skin are highly similar. Vascular lesions in VCA are also highlighted in this system and could impact graft outcome. The component score approach complements Banff 2007 grades and will enable the establishment of clinically significant thresholds

Minimally invasive mitral valve replacement: Port-access technique, feasibility, and myocardial functional preservation

AbstractObjective: This experiment examined the feasibility of minimally invasive port-access mitral valve replacement via a 2.5 cm incision. Methods: The study evaluated valvular performance and myocardial functional recovery in six mongrel dogs after port-access mitral valve replacement with a St. Jude Medical prosthesis (St. Jude Medical, Inc., St. Paul, Minn.). Femoro-femoral cardiopulmonary bypass and a balloon catheter system for myocardial protection with cardioplegic arrest (Heartport, Inc., Redwood City, Calif.) were used. The mitral valve was replaced through a 2.5 cm port in the left side of the chest, and the animals were weaned from bypass. Cardiac function was measured before and at 30 and 60 minutes after bypass. Left ventricular pressure and electrical conductance volume were used to calculate changes in load-independent indexes of ventricular function. Results: Each procedure was successfully completed. Recovery of left ventricular function was excellent at 30 and 60 minutes after bypass compared with the prebypass values for elastance (30 minutes = 4.04 ± 0.97 and 60 minutes = 4.27 ± 0.57 vs prebypass = 4.45 ± 0.96; p = 0.51) and for preload recruitable stroke work (30 minutes = 76.23 ± 4.80 and 60 minutes = 71.21 ± 2.99 vs prebypass = 71.23 ± 3.75; p = 0.45). Preload recruitable work area remained at 96% and 85% of baseline at 30 and 60 minutes (p = not significant). In addition, transesophageal echocardiography demonstrated normal prosthetic valve function, as well as normal regional and global ventricular wall motion. Autopsy revealed secure annular-sewing apposition and normal leaflet motion. Conclusions: These results suggest that minimally invasive mitral valve replacement using percutaneous cardiopulmonary bypass with cardioplegic arrest is technically reproducible, achieves normal valve placement, and results in complete cardiac functional recovery. Minimally invasive mitral valve replacement is now feasible, and clinical trials are indicated. (J Thorac Cardiovasc Surg 1997; 113:1022-31

Multiomic profiling of transplant glomerulopathy reveals a novel T-cell dominant subclass

Kidney transplant (KTx) biopsies showing transplant glomerulopathy (TG) (glomerular basement membrane double contours (cg) &gt; 0) and microvascular inflammation (MVI) in the absence of C4d staining and donor-specific antibodies (DSAs) do not fulfill the criteria for chronic active antibody–mediated rejection (CA-AMR) diagnosis and do not fit into any other Banff category. To investigate this, we initiated a multicenter intercontinental study encompassing 36 cases, comparing the immunomic and transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA-/C4d- with 22 classified as CA-AMR DSA+/C4d+ through novel transcriptomic analysis using the NanoString Banff-Human Organ Transplant (B-HOT) panel and subsequent orthogonal subset analysis using two innovative 5-marker multiplex immunofluorescent panels. Nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA+/C4d+ showed a higher glomerular abundance of natural killer cells and higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, interstitial fibrosis tubular atrophy, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA-/C4d-. Samples diagnosed with cg+MVI DSA-/C4d- displayed a higher glomerular abundance and activity of T cells (CD3+, CD3+CD8+, and CD3+CD8-). Thus, we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA-/C4d- have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell dominant phenotype.</p

Multiomic profiling of transplant glomerulopathy reveals a novel T-cell dominant subclass

Kidney transplant (KTx) biopsies showing transplant glomerulopathy (TG) (glomerular basement membrane double contours (cg) &gt; 0) and microvascular inflammation (MVI) in the absence of C4d staining and donor-specific antibodies (DSAs) do not fulfill the criteria for chronic active antibody–mediated rejection (CA-AMR) diagnosis and do not fit into any other Banff category. To investigate this, we initiated a multicenter intercontinental study encompassing 36 cases, comparing the immunomic and transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA-/C4d- with 22 classified as CA-AMR DSA+/C4d+ through novel transcriptomic analysis using the NanoString Banff-Human Organ Transplant (B-HOT) panel and subsequent orthogonal subset analysis using two innovative 5-marker multiplex immunofluorescent panels. Nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA+/C4d+ showed a higher glomerular abundance of natural killer cells and higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, interstitial fibrosis tubular atrophy, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA-/C4d-. Samples diagnosed with cg+MVI DSA-/C4d- displayed a higher glomerular abundance and activity of T cells (CD3+, CD3+CD8+, and CD3+CD8-). Thus, we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA-/C4d- have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell dominant phenotype.</p

Pros and cons for C4d as a biomarker

The introduction of C4d in daily clinical practice in the late nineties aroused an ever-increasing interest in the role of antibody-mediated mechanisms in allograft rejection. As a marker of classical complement activation, C4d made it possible to visualize the direct link between anti-donor antibodies and tissue injury at sites of antibody binding in a graft. With the expanding use of C4d worldwide several limitations of C4d were identified. For instance, in ABO-incompatible transplantations C4d is present in the majority of grafts but this seems to point at ‘graft accommodation’ rather than antibody-mediated rejection. C4d is now increasingly recognized as a potential biomarker in other fields where antibodies can cause tissue damage, such as systemic autoimmune diseases and pregnancy. In all these fields, C4d holds promise to detect patients at risk for the consequences of antibody-mediated disease. Moreover, the emergence of new therapeutics that block complement activation makes C4d a marker with potential to identify patients who may possibly benefit from these drugs. This review provides an overview of the past, present, and future perspectives of C4d as a biomarker, focusing on its use in solid organ transplantation and discussing its possible new roles in autoimmunity and pregnancy

Comparison of Evaluations for Heart Transplant Before Durable Left Ventricular Assist Device and Subsequent Receipt of Transplant at Transplant vs Nontransplant Centers

IMPORTANCE: In 2020, the Centers for Medicare & Medicaid Services revised its national coverage determination, removing the requirement to obtain review from a Medicare-approved heart transplant center to implant a durable left ventricular assist device (LVAD) for bridge-to-transplant (BTT) intent at an LVAD-only center. The association between center-level transplant availability and access to heart transplant, the gold-standard therapy for advanced heart failure (HF), is unknown. OBJECTIVE: To investigate the association of center transplant availability with LVAD implant strategies and subsequent heart transplant following LVAD implant before the Centers for Medicare & Medicaid Services policy change. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of the Society of Thoracic Surgeons Intermacs multicenter US registry database was conducted from April 1, 2012, to June 30, 2020. The population included patients with HF receiving a primary durable LVAD. EXPOSURES: LVAD center transplant availability (LVAD/transplant vs LVAD only). MAIN OUTCOMES AND MEASURES: The primary outcomes were implant strategy as BTT and subsequent transplant by 2 years. Covariates that might affect listing strategy and outcomes were included (eg, patient demographic characteristics, comorbidities) in multivariable models. Parameters for BTT listing were estimated using logistic regression with center-level random effects and for receipt of a transplant using a Cox proportional hazards regression model with death as a competing event. RESULTS: The sample included 22 221 LVAD recipients with a median age of 59.0 (IQR, 50.0-67.0) years, of whom 17 420 (78.4%) were male and 3156 (14.2%) received implants at LVAD-only centers. Receiving an LVAD at an LVAD/transplant center was associated with a 79% increased adjusted odds of BTT LVAD designation (odds ratio, 1.79; 95% CI, 1.35-2.38; P \u3c .001). The 2-year transplant rate following LVAD implant was 25.6% at LVAD/transplant centers and 11.9% at LVAD-only centers. There was an associated 33% increased rate of transplant at LVAD/transplant centers compared with LVAD-only centers (adjusted hazard ratio, 1.33; 95% CI, 1.17-1.51) with a similar hazard for death at 2 years (adjusted hazard ratio, 0.99; 95% CI, 0.90-1.08). CONCLUSIONS AND RELEVANCE: Receiving an LVAD at an LVAD-transplant center was associated with increased odds of BTT intent at implant and subsequent transplant receipt for patients at 2 years. The findings of this study suggest that Centers for Medicare & Medicaid Services policy change may have the unintended consequence of further increasing inequities in access to transplant among patients at LVAD-only centers

A primary care, multi-disciplinary disease management program for opioid-treated patients with chronic non-cancer pain and a high burden of psychiatric comorbidity

BACKGROUND: Chronic non-cancer pain is a common problem that is often accompanied by psychiatric comorbidity and disability. The effectiveness of a multi-disciplinary pain management program was tested in a 3 month before and after trial. METHODS: Providers in an academic general medicine clinic referred patients with chronic non-cancer pain for participation in a program that combined the skills of internists, clinical pharmacists, and a psychiatrist. Patients were either receiving opioids or being considered for opioid therapy. The intervention consisted of structured clinical assessments, monthly follow-up, pain contracts, medication titration, and psychiatric consultation. Pain, mood, and function were assessed at baseline and 3 months using the Brief Pain Inventory (BPI), the Center for Epidemiological Studies-Depression Scale scale (CESD) and the Pain Disability Index (PDI). Patients were monitored for substance misuse. RESULTS: Eighty-five patients were enrolled. Mean age was 51 years, 60% were male, 78% were Caucasian, and 93% were receiving opioids. Baseline average pain was 6.5 on an 11 point scale. The average CESD score was 24.0, and the mean PDI score was 47.0. Sixty-three patients (73%) completed 3 month follow-up. Fifteen withdrew from the program after identification of substance misuse. Among those completing 3 month follow-up, the average pain score improved to 5.5 (p = 0.003). The mean PDI score improved to 39.3 (p < 0.001). Mean CESD score was reduced to 18.0 (p < 0.001), and the proportion of depressed patients fell from 79% to 54% (p = 0.003). Substance misuse was identified in 27 patients (32%). CONCLUSIONS: A primary care disease management program improved pain, depression, and disability scores over three months in a cohort of opioid-treated patients with chronic non-cancer pain. Substance misuse and depression were common, and many patients who had substance misuse identified left the program when they were no longer prescribed opioids. Effective care of patients with chronic pain should include rigorous assessment and treatment of these comorbid disorders and intensive efforts to insure follow up