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.

TIM-1 signaling is required for maintenance and induction of regulatory B cells.

Apart from their role in humoral immunity, B cells can exhibit IL-10-dependent regulatory activity (Bregs). These regulatory subpopulations have been shown to inhibit inflammation and allograft rejection. However, our understanding of Bregs has been hampered by their rarity, lack of a specific marker, and poor insight into their induction and maintenance. We previously demonstrated that T cell immunoglobulin mucin domain-1 (TIM-1) identifies over 70% of IL-10-producing B cells, irrespective of other markers. We now show that TIM-1 is the primary receptor responsible for Breg induction by apoptotic cells (ACs). However, B cells that express a mutant form of TIM-1 lacking the mucin domain (TIM-1(Δmucin) ) exhibit decreased phosphatidylserine binding and are unable to produce IL-10 in response to ACs or by specific ligation with anti-TIM-1. TIM-1(Δmucin) mice also exhibit accelerated allograft rejection, which appears to be due in part to their defect in both baseline and induced IL-10(+) Bregs, since a single transfer of WT TIM-1(+) B cells can restore long-term graft survival. These data suggest that TIM-1 signaling plays a direct role in Breg maintenance and induction both under physiological conditions (in response to ACs) and in response to therapy through TIM-1 ligation. Moreover, they directly demonstrate that the mucin domain regulates TIM-1 signaling.

The emerging role of the TIM molecules in transplantation.

Since their discovery in 2001, the T-cell immunoglobulin mucin (TIM) family members have been shown to play important roles in the regulation of immune responses. The TIM family comprises of eight genes in the mouse, three of which are conserved in humans (TIM-1, TIM-3 and TIM-4). Initially, TIM-1 and TIM-3 were thought to be expressed solely on T cells. However, emerging data suggest a much broader expression pattern where their presence on APCs confers differing functions, including the ability to mediate phagocytosis. In contrast, TIM-4 is exclusively expressed on APCs. Together, the TIM molecules provide a functional repertoire for determining the fate of T-cell activation and differentiation. To date, much of the knowledge about the TIM family members has been garnered from the models of asthma, allergy and autoimmunity. More recently, data from experimental models of transplantation demonstrate that TIM family members also have a key role in alloimmunity. This review will serve to highlight the emerging data regarding this unique family of molecules and to identify their potential in transplantation tolerance.

Regulatory T cells in transplantation: what we know and what we do not know.

Current immunosuppressive regimens suppress alloimmunity by nonspecifically targeting T-cell proliferation, differentiation, and activation. In doing so, they have been effective in dramatically reducing rates of acute rejection and improving short-term allograft survival. However, this is often at the expense of overimmunosuppression. Furthermore, chronic rejection remains a significant problem. CD4(+)CD25(+)FoxP3(+) regulatory T cells (Treg) act to counterbalance effector mechanisms in immune homeostasis. Their function has been shown to be critical in autoimmune disease, transplantation, and allergy and inflammation. In this article, we will explore the current knowledge of Treg immunobiology in experimental models, as well as in human organ transplantation. The impact of current immunosuppressive agents on Tregs will be reviewed, and future promising targets for Treg-based therapies will be explored.

Evaluation of standardized versus individualized total parenteral nutrition regime for neonates less than 33 weeks gestation.

OBJECTIVE: To evaluate the difference in nutrient intakes and biochemical responses in newborn infants <33 weeks gestation who received standardized versus individualized total parenteral nutrition (TPN) regimes. METHOD: Comparison of nutrient intakes and daily biochemical responses in newborn infants <33 weeks gestation who received standardized regime versus those who received individualized TPN regimes from day 2 to day 7 of life. RESULTS: Twenty-seven infants in the standardized TPN group and 31 infants in the individualized TPN group were compared. There were no statistically significant differences (P > 0.05) between the two groups in gestation, birthweight, Clinical Risk Index for Babies scores, daily TPN volume intake and biochemical responses. Infants in the standardized TPN group received less sodium (P < 0.01) and no potassium on day 2 as required, more protein (P < 0.02) every day, and more calcium and phosphate (P < 0.02 from day 4). CONCLUSION: There were no significant clinical and statistical differences in biochemical responses in newborn infants <33 weeks gestation who received standardized versus individualized TPN regimes during the first week of life. The economic cost of TPN provision using standardized TPN formulation was approximately 30% lower.