B Cells Help Alloreactive T Cells Differentiate Into Memory T Cells

B cells are recognized as effector cells in allograft rejection that are dependent upon T cell help to produce alloantibodies causing graft injury. It is not known if B cells can also help T cells differentiate into memory cells in the alloimmune response. We found that in B‐cell‐deficient hosts, differentiation of alloreactive T cells into effectors was intact whereas their development into memory T cells was impaired. To test if B cell help for T cells was required for their continued differentiation into memory T cells, activated T cells were sorted from alloimmunized mice and transferred either with or without B cells into naïve adoptive hosts. Activated T cells cotransferred with B cells gave rise to more memory T cells than those transferred without B cells and upon recall, mediated accelerated rejection of skin allografts. Cotransfer of B cells led to increased memory T cells by enhancing activated CD4 T‐cell proliferation and activated CD8 T‐cell survival. These results indicate that B cells help alloreactive T‐cell differentiation, proliferation and survival to generate optimal numbers of functional memory T cells.     

Tacrolimus and cerivastatin pharmacokinetics and adverse effects after single and multiple dosing with cerivastatin in renal transplant recipients

AIMS: In contrast to cyclosporin, only limited information exists on the interaction potential between the immunosuppressive agent tacrolimus and HMG-CoA reductase inhibitors, which are metabolized via the cytochrome P450 system. The aim of this study was to investigate the pharmacokinetics, and adverse effects of cerivastatin combined with tacrolimus in renal transplant patients. METHODS: Ten patients with stable kidney graft functions and LDL-cholesterol serum concentrations > 110 mg dl-1 were included in the study. After an observation period of 3 months, cerivastatin (0.2 mg daily) was administered for an additional 3 months. Tacrolimus steady-state pharmacokinetics and cerivastatin single- and multiple-dose pharmacokinetics were determined. Lipid concentrations, routine laboratory parameters and adverse events were obtained and analysed throughout the study period of 6 months. RESULTS: Blood tacrolimus trough concentrations were not affected by cerivastatin (mean +/- SD 8.6 +/- 2.1 ng ml(-1) before, and 8.7 +/- 2.4 ng ml(-1) at day 90 of cerivastatin dosing, with a 95% confidence interval on the difference = 0.97, 1.08). The mean area under the blood concentration-time curve to 24 h (AUC(0,24 h)) for cerivastatin was 14.5 +/- 2.53 micro g l(-1) h(-1) at day 1 after starting treatment and 19.02 +/- 3.55 micro g l(-1) h(-1) (3 months later), resulting in a 35% higher (AUC(0,24 h)) compared with the first dose. Total cholesterol, LDL-cholesterol and triglyceride concentrations were significantly lowered by cerivastatin whereas no significant effect of cerivastatin on serum creatininkinase concentrations was observed and no adverse effects were documented. CONCLUSIONS: Tacrolimus increased the AUC(0, 24 h) of cerivastatin by a mean of 35% in renal transplant patients. Cerivastatin had no detectable effect on the pharmacokinetics of tacrolimus.     

The Roles of CD8 Central and Effector Memory T-Cell Subsets in Allograft Rejection

The contribution of secondary lymphoid tissue-homing central memory T cells (T_CM) and peripheral tissue-homing effector memory T cells (T_EM) to allograft rejection is not known. We tested whether T_EM is the principal subset responsible for allograft rejection due to the nonlymphoid location of target antigens. Skin allograft rejection was studied after transferring either CD8 T_CM or T_EM to wild-type mice and to mice that lack secondary lymphoid tissues. We found that CD8 T_CM and T_EM were equally effective at rejecting allografts in wild-type hosts. However, CD8 T_EM were significantly better than T_CM at rejecting allografts in the absence of secondary lymphoid tissues. CD8 T_CM were dependent upon secondary lymphoid tissues more than T_EM for optimal differentiation into effectors that migrate into the allograft. Recall of either CD8 T_CM or T_EM led to accumulation of T_EM after allograft rejection. These findings indicate that either CD8 T_CM or T_EM mediate allograft rejection but T_EM have an advantage over T_CM in immune surveillance of peripheral tissues, including transplanted organs.     

Modulation of murine T and B cell reactivity after short-term cadmium exposure in vivo

This study assessed early effects of short-term Cd exposure on T and B cell responsiveness. Spleen cells from mice injected s. c. with a daily dosage of 1 mg, 0.33 mg, or 0.11 mg Cd (as CdCl₂) per kg body weight for 5 days were examined for their potential to generate alloreactive T cells in a mixed lymphocyte reaction (MLR) and for mitogen reactivity to concanavalin A (Con A) in vitro. Spleen cells from the same mice were also assayed for the total number of IgM- and IgG-secreting B cells. Whereas alloreactivity was reduced, mitogen response to Con A was not different from controls or was even enhanced. The decrease in allogeneic MLR was dependent on the injected Cd dosage. No difference in susceptibility to Cd-induced effects was observed among the mouse strains tested, i.e. BALB/c, DBA/2, C57BL/6, and C3H/He. Co-cultivation of spleen cells, obtained from Cd-treated mice that exhibited deficient T cell reactivity, with splenic responder cells from untreated mice resulted in dose-dependent suppression of the normal MLR. These results indicate that the harmful effects of Cd on the immune system include the inhibition of antigen-specific T cell responses by the activation of an antigen non-specific suppressor system. In contrast to the suppressed allogeneic MLR, the same spleen cell populations showed augmented numbers of IgM- and IgG-antibody producing cells.Abbreviations Cd cadmium - Con A concanavalin A - CTL cytotoxic T lymphocyte - HBSS Hank's Balanced Salt Solution - LPS lipopolysaccharide - MLR mixed lymphocyte reaction - MMC mitomycin C - MT metallothionein - PFC plaque forming cell - PHA phytohemagglutinin - PMA phorbolmyristic acid - SI stimulation index - SPF specific pathogen-free - SRBC sheep red blood cells     

Inflammation Causes Resistance to Anti‐CD20–Mediated B Cell Depletion

B cells play a central role in antibody‐mediated rejection and certain autoimmune diseases. However, B cell–targeted therapy such as anti‐CD20 B cell–depleting antibody (aCD20) has yielded mixed results in improving outcomes. In this study, we investigated whether an accelerated B cell reconstitution leading to aCD20 depletion resistance could account for these discrepancies. Using a transplantation model, we found that antigen‐independent inflammation, likely through toll‐like receptor (TLR) signaling, was sufficient to mitigate B cell depletion. Secondary lymphoid organs had a quicker recovery of B cells when compared to peripheral blood. Inflammation altered the pharmacokinetics (PK) and pharmacodynamics (PD) of aCD20 therapy by shortening drug half‐life and accelerating the reconstitution of the peripheral B cell pool by bone marrow–derived B cell precursors. IVIG (intravenous immunoglobulin) coadministration also shortened aCD20 drug half‐life and led to accelerated B cell recovery. Repeated aCD20 dosing restored B cell depletion and delayed allograft rejection, especially B cell–dependent, antibody‐independent allograft rejection. These data demonstrate the importance of further clinical studies of the PK/PD of monoclonal antibody treatment in inflammatory conditions. The data also highlight the disconnect between B cell depletion on peripheral blood compared to secondary lymphoid organs, the deleterious effect of IVIG when given with aCD20 and the relevance of redosing of aCD20 for effective B cell depletion in alloimmunity.     

Langerhans cells are not required for efficient skin graft rejection

The mechanism of skin allograft rejection has been thought to require presentation of graft antigen by resident epidermal Langerhans cells (LCs). We have previously engineered mice that have a selective and constitutive absence of epidermal LCs. By using donor skin from these LC-deficient mice, we show that LCs are not required for rejection of major (FVB --> B6) or minor (H-Y, male --> female on B6 background) antigen-mismatched skin grafts. On the FVB background, where H-Y mismatched grafts are normally maintained indefinitely, grafts lacking LCs are efficiently rejected. Thus, LCs in the donor graft are required for long-term skin engraftment, which supports a regulatory role for LCs in skin graft acceptance.