Memory T cell–mediated rejection is mitigated by FcγRIIB expression on CD8+ T cells

Donor‐reactive memory T cells generated via heterologous immunity represent a potent barrier to long‐term graft survival following transplantation because of their increased precursor frequency, rapid effector function, altered trafficking patterns, and reduced reliance on costimulation signals for activation. Thus, the identification of pathways that control memory T cell survival and secondary recall potential may provide new opportunities for therapeutic intervention. Here, we discovered that donor‐specific effector/memory CD8⁺ T cell populations generated via exposure to acute vs latent vs chronic infections contain differential frequencies of CD8⁺ T cells expressing the inhibitory Fc receptor FcγRIIB. Results indicated that frequencies of FcγRIIB‐expressing CD8⁺ donor‐reactive memory T cells inversely correlated with allograft rejection. Furthermore, adoptive T cell transfer of Fcgr2b^?/? CD8⁺ T cells resulted in an accumulation of donor‐specific CD8⁺ memory T cells and enhanced recall responses, indicating that FcγRIIB functions intrinsically to limit T cell CD8⁺ survival in vivo. Lastly, we show that deletion of FcγRIIB on donor‐specific CD8⁺ memory T cells precipitated costimulation blockade‐resistant rejection. These data therefore identify a novel cell‐intrinsic inhibitory pathway that functions to limit the risk of memory T cell–mediated rejection following transplantation and suggest that therapeutic manipulation of this pathway could improve outcomes in sensitized patients.     

Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulation

After a brief period of antigenic stimulation, T cells become committed to a program of autonomous expansion and differentiation. We investigated the role of antigen-specific T cell precursor frequency as a possible cell-extrinsic factor impacting T cell programming in a model of allogeneic tissue transplantation. Using an adoptive transfer system to incrementally raise the precursor frequency of antigen-specific CD8(+) T cells, we found that donor-reactive T cells primed at low frequency exhibited increased cellular division, decreased development of multifunctional effector activity, and an increased requirement for CD28- and CD154-mediated costimulation relative to those primed at high frequency. The results demonstrated that recipients with low CD4(+) and CD8(+) donor-reactive T cell frequencies exhibited long-term skin graft survival upon CD28/CD154 blockade, whereas simultaneously raising the frequency of CD4(+) T cells to approximately 0.5% and CD8(+) T cells to approximately 5% precipitated graft rejection despite CD28/CD154 blockade. Antigenic rechallenge of equal numbers of cells stimulated at high or low frequency revealed that cells retained an imprint of the frequency at which they were primed. These results demonstrate a critical role for initial precursor frequency in determining the CD8(+) T cell requirement for CD28- and CD154-mediated costimulatory signals during graft rejection.     

A simple device to reproduce the spatial orientations of the thorax and transducer for serial M-mode and two-dimensional echocardiograms

We have described a device consisting of three circular levels for locating the spatial orientations of the thorax and a transducer that can be used to reproduce the path of the sonic beam through the heart.     

Quality assessment and quality control of echocardiographic performance in a large multicenter international study: Valsartan in heart failure trial (Val-HeFT).

OBJECTIVE: To qualify 302 multinational echocardiography sites to record and read serial studies and to monitor quality in 5010 patients randomized into Valsartan in Heart Failure Trial (Val-HeFT). BACKGROUND: Decentralized echocardiography reading is unprecedented in large clinical trials. METHODS: Single and duplicate recordings, and triplicate readings of echocardiographic variables were submitted to 3 core laboratories. Quality of recording was defined with a 16-point scoring system; accuracy of reading by agreement with core readings; reproducibility by agreement between the duplicate studies. RESULTS: Seventy-five percent of initial submissions were approved for recording, and 50% for reading. Resubmissions were evaluated until approval. Initial scores of sites approved with 1 versus 2 submissions differed, 13.8 +/- 1.4 versus 10.6 +/- 2.0, P <.001; final score was similar, 13.4 +/- 1.6, P = ns. Initial score of sites approved after 3 or more submissions differed, 9.5 +/- 1.9, P <.001; final score improved to 12.7 +/- 1.9, but remained lower, P <.001. Expressed as 95% limits of agreement (mean difference +/- 1.96 x SD), accuracy = -0.04 +/- 0.74 cm for left ventricular internal end-diastolic diameter (LVIDd); -0.29 +/- 14.3% for ejection fraction (EF); reproducibility = 0.00 +/- 0.53 cm for LVIDd; -0.25 +/- 8.3% for EF. Quality of random sampling at baseline, 4, 12, and 18 months showed recording scores of 11.7 +/- 2.7, 12.3 +/- 2.4, 12.1 +/- 2.2, and 11.4 +/- 2.0, P =.24. Power analysis revealed differences of 0.09 cm for LVIDd, and 0.86% for EF detectable with a power of 90% and alpha of 5%. CONCLUSION: The qualifying process improved echocardiography recording and reading to bring 95% of the sites to an equivalent level of quality. Monitoring quality found that recording quality and reading accuracy were maintained 18 months into the trial. Reproducibility, given the large sample size, will be able to detect small changes in LVIDd and EF.     

LFA-1 blockade induces effector and regulatory T-cell enrichment in lymph nodes and synergizes with CTLA-4Ig to inhibit effector function

Despite encouraging results using lymphocyte function antigen-1 (LFA-1) blockade to inhibit BM and solid organ transplantation rejection in nonhuman primates and humans, the precise mechanisms underlying its therapeutic potential are still poorly understood. Using a fully allogeneic murine transplantation model, we assessed the relative distribution of total lymphocyte subsets in untreated versus anti-LFA-1-treated animals. Our results demonstrated a striking loss of naive T cells from peripheral lymph nodes, a concomitant gain in blood after LFA-1 blockade, and a shift in phenotype of the cells remaining in the node to a CD62LloCD44hi profile. We determined that this change was due to a specific enrichment of activated, graft-specific effectors in the peripheral lymph nodes of anti-LFA-1-treated mice compared with untreated controls, and not to a direct effect of anti-LFA-1 on CD62L expression. LFA-1 blockade also resulted in a dramatic increase in the frequency of CD4+ FoxP3+ regulatory T cells in graft-draining nodes. Our results suggest that the differential impact of LFA-1 blockade on the distribution of naive versus effector and regulatory T cells may underlie its ability to inhibit alloreactive T-cell responses after transplantation.     

Signs and symptoms in chronic heart failure: relevance of clinical trial results to point of care-data from Val-HeFT

BACKGROUND: Clinical trials emphasize mortality and morbidity endpoints. AIMS: To bring relevance of trial results to point of care by examining the prognostic and therapeutic value of individual signs and symptoms (S&S). METHODS: We analysed data from 5010 patients with stable chronic heart failure and left ventricular dysfunction who were participants in the Val-HeFT study. Individual S&S were stratified by severity. Treatment differences between valsartan and placebo were analysed by S&S strata at baseline and endpoint by logistical regression, and an overall S&S score by ANCOVA. Hazard ratios of S&S strata were calculated for mortality and heart failure hospitalisation. Prognostic contributions of S&S to other variables were determined by multivariate analysis. RESULTS: At endpoint, there were significantly fewer valsartan and more placebo patients with severe symptoms. Over time, improvement in the S&S overall score was significantly more favourable for valsartan than placebo. S&S strata were significantly predictive of risk for hospitalisation and death. S&S were each independent and incremental predictors of mortality compared to other variables. Symptom strata separated out moderately symptomatic patients with a mortality rate which was intermediate between that for NYHA Class II and III. CONCLUSION: Risk stratification of individual S&S defined prognosis, identified patients with an intermediate mortality between Class II and III, and treatment benefits of valsartan over placebo.     

Incremental prognostic value of changes in B-type natriuretic peptide in heart failure

Purpose

B-type natriuretic peptide is one of the most sensitive and specific biohumoral markers of heart failure. We hypothesized that B-type natriuretic peptide changes during treatment of heart failure may provide independent information on disease progression and outcome in patients enrolled in the Val-HeFT trial.

Methods

Patients were divided into four groups according to concentrations of B-type natriuretic peptide at baseline versus 4 months (n = 3740) or 12 months (n = 3343), with respect to the baseline median (97 pg/mL): low→low (stable below median, 44%-46%), high→high (stable above median, 32%-37%), high→low (above to below median, 12%-14%), and low→high (below to above median, 6%-9%). Cox multivariate regression analysis was used to assess the risk of death and morbidity, with adjustment for baseline B-type natriuretic peptide concentrations.

Results

Patients who improved their B-type natriuretic peptide at 4 months (high→low) had a similar risk for mortality (hazard ratio = 1.191, 95% confidence interval [CI] 0.870-1.631, P =.2746) compared with the low→low patients. Conversely, patients who worsened in their B-type natriuretic peptide (low→high) had a risk for mortality (hazard ratio 2.578, CI, 1.861-3.571, P <.0001) higher than patients in the low→low group, and indistinguishable from the high→high group. Worsening of B-type natriuretic peptide (low→high) was associated with 0.03 cm/m² increase in left ventricular end-diastolic diameter, whereas it decreased by 0.10 cm/m² in high→low and low→low groups (P <.001).

Conclusions

Changes in B-type natriuretic peptide over time with respect to a threshold value of 97 pg/mL convey an independent and additional prognostic value compared with a single determination of B-type natriuretic peptide in a large population of patients with chronic symptomatic heart failure and might be helpful in the management of these patients.