Combination of Donor-Specific Blood Transfusion With Anti-CD28 Antibody Synergizes to Prolong Graft Survival in Rat Liver Transplantation

Selective expansion of memory CD4+ T cells by mitogenic human CD28 generates inflammatory cytokines and regulatory T cells

“…The clinical use of It now appears that mitogenic CD28 mAb induce high levels of inflammatory cytokines both in vivo and in vitro, challenging the clinical efficacy of these antibodies. The groups of Hünig and Hanke reported selective expansion of regulatory T cells by mitogenic rat or human CD28 [6][7][8][9][10][11][12][13], yet the mitogenic antihuman CD28 caused a cytokine storm in the Phase I in vivo trial [15,16]. Our study provides a plausible explanation for this contradiction; (i) stimulation through mitogenic CD28 activates pathogenic effector T cells as well as protective regulatory T cells.…”

“…The groups of Hünig and Hanke [6][7][8][9][10][11][12][13] extensively characterized the mitogenic anti-rat CD28 mAb JJ316, which preferentially expanded regulatory T cells (Treg) and induced anti-inflammatory cytokines in vitro and in vivo with therapeutic abilities in vivo. In particular, JJ316 prevented EAE and adjuvant arthritis in rats [6,10].…”

FR104, an Antagonist Anti-CD28 Monovalent Fab’ Antibody, Prevents Alloimmunization and Allows Calcineurin Inhibitor Minimization in Nonhuman Primate Renal Allograft

“…The theoretical advantage of selective CD28 blockade as compared with CD80/86 antagonists has been further reinforced by the recent discovery of the inhibitory interaction between PD-L1 and CD80 (19,20) and the activation interaction between CD28 and ICOSL (21). Previous work has shown that selective targeting of CD28 itself inhibits autoimmunity (22,23) and graftversus-host disease (13,17,18,24,25), prevents acute and chronic allograft rejection in rodents (15,(26)(27)(28)(29)(30)(31), and induces regulatory cells (12,15,28,(31)(32)(33) and immune tolerance in a CTLA-4 dependent manner (15). In nonhuman primate (NHP) kidney and heart transplantation, we reported that, with a pilot drug, selective CD28 blockade also inhibits acute and chronic rejection and promotes Tregs in association with CNI (12).…”

Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412

“…18,19 The latter property has been exploited in a plethora of rat and mouse models of autoimmunity, inflammation, and transplantation, with extremely encouraging results. [20][21][22][23][24][25][26][27][28][29][30][31] It was therefore a shock when TGN1412, a human CD28SA of the IgG4 subclass, caused a life-threatening cytokine release syndrome (CRS) during a first-in-man trial in March 2006. 32 This tragic outcome was unexpected not only because of the benign behavior of CD28SA in analogous rodent models, but also because TGN1412 itself was well tolerated in cynomolgous monkeys.…”