Monoclonal Antibody Treatment to Prolong the Secondary Cardiac Allograft Survival in Alloantigen-primed Mice

Abstract

We have previously shown that costimulation blockade using a combination of monoclonal antibodies (mAbs) – CTLA4Ig, antibodies to CD154, LFA‐1, and OX40L – can induce tolerance of cardiac allografts in mice with adoptively transferred CD4+ memory T cells [1]. However, the effect of costimulatory blockade in secondary allograft rejection has not been studied. B6 mice that rejected BALB/c skin grafts for more than 4 weeks (defined as alloantigen‐primed mice) were used as recipients. The recipient mice were treated with the mAbs to CD154, LFA‐1, OX40L, and CD122 on days 0, 2, 4, and 6 after the secondary transplantation of BALB/c heart. The mean survival time (MST) of secondary cardiac allografts in rats treated with antibodies to CD154 and LFA‐1 (2‐antibodies approach) and those treated with antibodies to CD154, LFA‐1, OX40L, and CD122 (4‐antibodies approach) was greater than that of the controls (MST = 6.7 days, 22.2 days, and 3.2 days, respectively). The 4‐antibodies approach prevented lymphocytic infiltration in the grafts, inhibited memory T‐cells proliferation in the spleen, increased IL‐10 secretion in the serum, and enhanced the expression of CD4+ Foxp3+ regulatory T cells (Tregs) in spleen. Expression levels of alloreactive antibodies were high in the recipient mice of experimental and control groups. Inhibiting the memory T cells by costimulation blockade extended allograft survival in secondary transplant models but could not induce tolerance of graft. Alloreactive antibodies may participate in alloresponse and play an important role in secondary cardiac allograft rejection.

Combination of monoclonal antibodies with DST inhibits accelerated rejection mediated by memory T cells to induce long-lived heart allograft acceptance in mice

“…It was likely that when memory T cells function is inhibited, activated effector T cells may still attack the grafts. According to previously published studies, the treatment with anti-CD40L/LFA-1 can also notably inhibit the recruitment of effector T cells into the graft and prolong primary graft survival time, but it has little effect on alloreactive memory T cells [18][19][20][21]. Interestingly, our results show that compared to anti-CD44/CD70/DST, the anti-CD40L/LFA-1/DST treatment prolonged allograft survival in the presence of memory T cells (MST = 49.5 d), and there maybe two reasons for this phenomenon.…”

“…Therefore, 5-combination treatment is a novel strategy for inhibiting rejection mediated by memory T cells. However, memory B cells also contributed to the rejection of allografts in alloantigen-primed mice [20]. The effect of anti-CD40L/LFA-1/CD44/CD70/DST treatment on memory B cells and donor-specific antibody responses will be investigated in our future research.…”

Integrin Antagonists Prevent Costimulatory Blockade-Resistant Transplant Rejection by CD8+ Memory T Cells

“…These findings are of obvious translational significance, as humanized monoclonal antibodies against both LFA-1 and VLA-4 have been developed and FDA-approved for clinical use against autoimmune diseases. In contrast, several groups have explored other regimens to improve the efficacy of CoB against memory alloresponses, but these have employed reagents that are not clinically relevant (42, 51, 52). …”

CD44/CD70 Blockade and Anti‐CD154/LFA‐1 Treatment Synergistically Suppress Accelerated Rejection and Prolong Cardiac Allograft Survival in Mice

“…To develop a more effective treatment for controlling the accelerated rejection mediated by memory T cells, we selected classical adoptive transfer models that exclude the interference of memory B cells and used different combinations of antibodies to determine their effects on allograft survival. Two well‐known monoclonal antibodies (mAbs) in transplant studies, anti‐CD154 and anti‐LFA‐1, were combined to target effector T cells [16], and the anti‐CD44/CD70 combination was used to target memory T cells.…”