Simultaneous inhibition of B7 and LFA‐1 signaling prevents rejection of discordant neural xenografts in mice lacking CD40L

Abstract

: Transplantation of embryonic human neural tissue can restore dopamine neurotransmission and improve neurological function in patients with Parkinson's disease. Logistical and ethical factors limit the availability of human embryonic allogeneic tissue. Embryonic xenogeneic neural tissue from porcine donors is an alternative form of donor tissue, but effective immunomodulatory techniques are warranted for neural xenotransplantation to become clinically feasible. We transplanted embryonic porcine ventral mesencephalic tissue into the brains of adult untreated C57BL/6 mice, untreated CD40L‐/–mice and CD40L‐/–mice that received injections of anti‐LFA‐1, CTLA4Ig or both compounds. Double‐treated CD40L‐/–mice had large grafts with high numbers of dopaminergic neurons 4 wk after transplantation. The grafts were completely devoid of lymphocytes, macrophages and activated microglia. Untreated C57BL/6 mice had rejected their grafts. Untreated CD40L‐/–mice and CD40L‐/–mice treated with monotherapy of anti‐LFA‐1 or CTLA4Ig had smaller grafts and more microglial and lymphocytic infiltration than double‐treated CD40L‐/–mice. We conclude that immunomodulation with concomitant inhibition of LFA‐1 and B7 signaling in the perioperative period in CD40L‐/–mice prevented the rejection of discordant neural xenografts. The treatment most likely reduced antigen presenting capacity and interfered with the costimulatory signaling needed for T cell activation to occur.

Immune problems in central nervous system cell therapy

“…Antibodies against T-cell receptor anti-TCR␣␤ and T cells have been used to enhance the survival of intracerebral neural xenografts in rats. 38,39 Larsson and colleagues 40,41 have also explored the use of blockers to T-cell costimulatory molecules as an alternative route to tolerance, therefore highlighting the value of targeting this arm of the immune response for xenograft survival.…”

“…Conventional immunosuppressive drugs used as monotherapy (e.g., cyclosporin A or tacrolimus) do not protect grafts effectively, [65][66][67] but this can be improved if combined with other drugs such as prednisolone. 65 Short courses of treatment with molecules that block T-cell costimulation [CD40L, LFA1, and CTLA4Ig (40,41)] have resulted in very good graft survival in mice, although long-term studies are needed to determine whether this therapy could be used clinically. 41 The role for humoral factors in xenograft rejection has been addressed using a number of different approaches.…”

Induction of operational tolerance to discordant dopaminergic porcine xenografts1

“…Studies have shown that a combination of immunosuppressive drugs can be used to overcome the rejection process of porcine xenografts in rats (11,12), but not in mice. No treatment so far has led to any significant graft survival in mice except blocking the costimulatory signals lymphocyte function antigen (LFA)-1 and B7 in CD40L-deficient mice (13). A short-term blockade of costimulatory signals could also have fewer side effects than chronic long-term immunosuppression with drugs such as prednisolone and cyclosporine.…”

“…The implantation technique has been described in detail previously (13). The ventral mesencephalons from 26-day-old pig embryos (Swedish LandraceϫYorkshire and Hampshire) were harvested in Hank's balanced salt solution (Gibco, Life Tech, Uppsala, Sweden) with the addition of 3.0 M tirilazad (Pharmacia and Upjohn, Kalamazoo, MI).…”

Low Immunogenic Potential of Human Neural Stem Cells

“…Antibodies against T-cell receptor anti-TCR and T cells have been used to enhance the survival of intracerebral neural xenografts in rats (Okura et al 1997;Wood et al 1996). Also the use of blockers of T-cells costimulatory molecules have been explored as alternative route to tolerance, therefore highlighting the value of targeting this arm of the immune response for xenograft survival (Larsson et al 2003;Larsson et al 2002).…”