CD27+ B cells from a subgroup of common variable immunodeficiency patients are less sensitive to apoptosis rescue regardless of interleukin-21 signalling.

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinaemia and recurrent infections. Although the underlying cause is unknown, B cells from most CVID patients fail to differentiate to memory or plasma cells. We investigated if increased apoptosis could influence the fate of B cells. For this purpose we activated purified B lymphocytes of CVID patients with a surrogate T-dependent (anti-CD40) or T-independent [cytosine-phosphate-guanosine oligodeoxynucleotides (CpG-ODN) or anti-immunoglobulin (Ig)M)] stimulus with or without interleukin (IL)-21. We found that CD27(+) B cells were more sensitive than CD27(-) B cells to spontaneous apoptosis and less sensitive to rescue from apoptosis. The addition of IL-21 down-modulated the protective effect of all the stimuli on CD27(-) B cells and the protective effect of CpG-ODN and anti-IgM on CD27(+) B cells. In contrast, IL-21 rescued unstimulated CD27(-) B cells and improved the rescue of anti-CD40-stimulated CD27(+) B cells. When we compared patients and controls, mainly CD27(+) B cells from MB0 patients were less sensitive to rescue from apoptosis than those from MB1 patients and controls after activation, irrespective of the IL-21 effect. Increased apoptosis during an immune response could result in lower levels of immunoglobulin production in these patients.

The potential impact of substitutive therapy with intravenous immunoglobulin on the outcome of heart transplant recipients with infections.

Hypogammaglobulinemia has been proposed to be a risk factor for infection after heart transplantation (OHT). Infection is a leading cause of morbility and mortality among these patients. In a retrospective study we analyzed the impact of substitutive therapy with nonspecific intravenous immunoglobulin (IVIG) on the outcomes of heart transplant patients with infections. We analyzed the outcome of 123 consecutive heart transplant recipients in our center from June 1996 to November 2005. Their mean age was 53 years (range = 22 to 69 years), and the mean follow-up = 51 months, (range = 1 to 124 months). Twenty-nine patients with hypogammaglobulinemia (mean serum immunoglobulin G levels = 480 mg/dL) experienced severe infections due to cytomegalovirus (CMV) disease, n = 4; CMV disease + another infection, n = 6; CMV infection, n = 4; CMV infection + other infection, n = 3; pulmonary nocardiosis, n = 2; recurrent pneumonia, n = 2; clostridium-difficile-associated diarrhea, n = 2; pulmonary tuberculosis, n = 1; bacterial infections, n = 5. They were treated with IVIG (400 mg/kg every 21 days) with the goal to reach normal serum immunoglobulin G levels (>700 mg/dL). Overall (n = 123), a logistic regression analysis showed IVIG therapy to be associated with a decreased risk of death [odds ratio (OR) = 0.204, 95% confidence interval (CI) = 0.04 to 0.92, P = .03]. Among patients who developed infections during follow-up (n = 70), IVIG therapy was also associated with a lower risk of death (OR = 0.104, CI = 0.02 to 0.50, P = .0047). When we stratified patients with CMV disease (n = 24) according to the presence (n = 10) or absence (n = 14) of IVIG therapy, the mortality rate of IVIG-treated patients was 20% versus 71% for non-IVIG treated patients [OR = 0.06, CI = 0.0060 to 0.63, P = .01]. The use of nonspecific IVIG in OHT with hypogammaglobulinemia and infections might reduce the risk of death. Randomized studies in a larger cohort of patients are necessary to confirm these results.

Impaired anti-pneumococcal polysaccharide antibody production and invasive pneumococcal infection following heart transplantation.

An increased risk of invasive pneumococcal infection has been described among adult heart transplant (HT) recipients. Vaccination has been recommended before HT but the appropriate time for revaccination is not known. In a preliminary analysis of a prospective study involving a cohort of 32 HT recipients receiving daclizumab and triple immunosuppresion therapy, a progressive decline in pneumococcal polysaccharide antibody (anti-PPS) levels was observed during the first year after HT. One of the patients who was found to have a decrease in the levels of anti-PPS developed severe pneumococcal meningitis 20 months after HT. Before HT he had received non-conjugated 23-valent pneumococcal vaccine and showed a normal post-immunization anti-PPS production. The data suggest that long-term immunologic monitoring might be useful to recognize impairment of antibody responses under immunosuppressive therapy in HT.

Kinetics of functionally distinct T-lymphocyte subsets in heart transplant recipients after induction therapy with anti-CD25 monoclonal antibodies.

T cells are involved in the maintenance of immunocompetence and in the development of alloimmune responses in solid organ transplant recipients. The kinetics of functionally distinct T-cell subsets in peripheral blood has received little attention in the field of heart transplantation. We performed a simultaneous analysis of the maturation, activation, and regulatory profiles of T cells using 4-color flow cytometry in a study of 77 heart recipients. Induction therapy included 2 doses of anti-CD25 monoclonal antibodies (daclizumab). Lymphocyte subsets were prospectively evaluated at different times before and up to 1 year after transplantation in 46 heart recipients. A separate cross-sectional study was performed in 33 heart recipients who had received a transplant more than 1 year previously to evaluate abnormalities persisting in the long term. As compared with baseline values, a decrease in regulatory CD4+ T-cell percentages (CD4+CD127lowCD25highFoxP3+) was observed from day 7 to 12 months after transplantation. Interestingly, T cells expressing the beta chain of IL-2 (CD122+) remained stable during the first 3 months. A significant decrease in the activation status of CD4 T cells was documented from day 7 to 1 year after transplantation, while the activation status of CD8+ T cells remained stable during follow-up. Compared with values for healthy controls (n=36), higher CD8+ terminally differentiated effector memory percentages (CD8+CD45RA+CCR7-) were observed from baseline up to more than 1 year after transplantation. Rejection was associated with higher levels of these cells during the first 6 months after transplant. We characterized the abnormalities in distinct functional T-cell subsets at different times before and after heart transplantation. Some of these abnormalities should be further investigated as biomarkers of clinical complications.

Immunophenotypic profile of T cells in common variable immunodeficiency: is there an association with different clinical findings?

BACKGROUND: A system based on the B-cell phenotype has recently been proposed to classify patients suffering from common variable immunodeficiency (CVID). Immunophenotypic T-cell abnormalities have also been correlated with clinical findings, although they have never been used in classification strategies. OBJECTIVE: To simultaneously assess T and B-cell subset abnormalities in CVID patients and their relationship with clinical findings. To identify potential immunophenotypic T-cell abnormalities that could be further evaluated in multicenter studies. PATIENTS AND METHODS: Peripheral blood lymphocytes from 21 CVID patients and 21 healthy donors were stained for T and B-cell subsets, analyzed by flow cytometry, and correlated with clinical characteristics. RESULTS: Patients classified as MB0 (CD19/CD27+ < 11 %) showed higher percentages of CD4/ CD45RA (87 % vs 67 %, p = 0.028) and lower percentages of CD8/CD45RA+CCR7+ (10 % vs 26 %, p = 0.028) and CD4/CD25+ T-cells (36 % vs 62 %, p = 0.034) than MB2 patients. Even though our cohort was small, we observed a higher prevalence of distinct clinical complications of CVID in patients with B and T-cell abnormalities. Nonmalignant lymphoproliferative disorders and IgG hypercatabolism were more frequently observed in MB0 patients. A higher prevalence of splenomegaly was observed among CVID patients with increased levels of CD4/CD45RA, activated CD4/CD38+DR+, CD8/DR+, and CD8/CD38+ T-cells, as well as in those with lower percentages of CD4/CD45RA+CCR7+ and CD4/CD25+ T-cells. Lymphoproliferative disorders were more prevalent among CVID patients with higher CD4/CD45RA percentages. CONCLUSION: The study of T-cell subsets warrants further evaluation as a potential tool to better identify CVID patients with distinct clinical profiles.

The potential role of T-cell memory distribution as predisposing factor for rejection in heart transplant recipients.

CD4 T cells play a significant role in the pathogenesis of rejection, providing help to alloreactive CD8 and B cells, however, the exact contribution of each memory compartment in vivo has not been defined. They are also important for the maintenance of tolerance due to regulatory activity of specialized subsets. In this study, we assessed changes in frequencies of functionally distinct lymphocyte subsets of peripheral blood (PBLs) in 26 heart transplant recipients (HT) in association with rejection episodes. Patients who developed rejection (n = 7), namely Grade 3B (n = 1), 3A (n = 4), or 2 (n = 2), in comparison with those with stable graft function displayed at baseline (pre-HT) higher percentages of naive (CCR7+CD45RA+) CD4 T cells (median 48 vs 36.6%; P = .035) and lower percentages of central memory (CCR7+CD45RA-) CD4 T cells (33.3 vs 46.5%; P = .035). At 30 days post-HT, CD4/CD127(low)FoxP3+ T cells were significantly reduced among patients with rejection episodes (0.84 vs 2.15%; P = .042). CD8 final effector T cells were increased at 90 days post-HT among those patients who experienced rejection (TEM2: 60.8 vs 31.9%; P < .1), at the expense of shrinking CD8 central memory compartment (TCM: 8.6 vs 12.9%; P = .046). The potential role of T-cell memory distribution should be further evaluated in HT patients as possible markers to discriminate patients at risk for rejection.