Immune parameters relevant to neural xenograft survival in the primate brain

Abstract

The lack of supply and access to human tissue has prompted the development of xenotransplantation as a potential clinical modality for neural cell transplantation. The goal of the present study was to achieve a better understanding of the immune factors involved in neural xenograft rejection in primates. Initially, we quantified complement mediated cell lysis of porcine fetal neurons by primate serum and demonstrated that anti-C5 antibody treatment inhibited cell death. We then developed an immunosuppression protocol that included in vivo anti-C5 monoclonal antibody treatment, triple drug therapy (cyclosporine, methylprednisolone, azathioprine) and donor tissue derived from CD59 or H-transferase transgenic pigs and applied it to pig-to-primate neural cell transplant models. Pre-formed alphaGal, induced alphaGal and primate anti-mouse antibody (PAMA) titers were monitored to assess the immune response. Four primates were transplanted. The three CD59 neural cell recipients showed an induced anti-alphaGal response, whereas the H-transferase neural cell recipient exhibited consistently low anti-alphaGal titers. Two of these recipients contained surviving grafts as detected by immunohistochemistry using selected neural markers. Graft survival correlated with high dose cyclosporine treatment, complete complement blockade and the absence of an induced PAMA response to the murine anti-C5 monoclonal antibodies.

Immune problems in central nervous system cell therapy

“…68 Transgenic porcine VM tissue, expressing either the human complement inhibitor CD59 or human ␣-1,2-fucosyltransferase in combination with a recipient treatment with anti-C5 antibodies (H transferase), survives up to 12 weeks in parkinsonian primates. 69 However, the level of expression of these human complement regulatory proteins is generally low in transgenic embryonic pig brain. 70 An alternative mode of interfering with the rejection process provoked by porcine neural tissue is to block MHC class I molecules in the donor tissue by immunomasking with F(ab) 2 antibody fragments, although the level of expression of this epitope is very low in embryonic porcine neural tissue.…”

Remyelination of the nonhuman primate spinal cord by transplantation of H‐transferase transgenic adult pig olfactory ensheathing cells

“…Although anti-αGal antibody reactivity and complement activation certainly contribute to xenogeneic organ rejection (25,26), cells transplanted into the CNS are also susceptible to humoral-mediated rejection (27). Cicchetti et al (27) showed that an induced anti-αGal antibody response to cells transplanted in the CNS was a parameter for tissue rejection and that the induced anti-αGal response was similar to the response observed in whole organ transplantation, i.e., three-to five-fold increase within the first 2 wk after transplantation. In addition, an induced anti-αGal antibody response was completely absent in an HT neuron transplant recipient.…”

“…Examples include the treatment of Parkinson's disease patients with embryonic porcine mesencephalic neurons (28) and the use of porcine hepatocytes for liver support systems in cases of acute liver failure (29). Many porcine cell types potentially useful for transplantation, such as cardiomyocytes for damaged heart muscle (30) or OECs for axonal repair (4), would be expected to trigger a humoral and cellular immune response (25)(26)(27). Therefore, the demonstration that genetically engineered pig OECs, modified to resist humoral immunity, exhibit characteristic OEC phenotypic properties and can repair demyelinated primate spinal cord lesions reinforces the potential utility of transgenic porcine tissues for human cell therapy.…”

Mesenchymal Stem Cell-Based Therapies for Parkinson’s Disease: Progress, Controversies and Lessons for the Future

“…This immunosuppressive regimen yielded decreased microglial accumulation and increased survival of Müller SCs. Other studies investigating xenograft survival in the CNS have found promising outcomes through the use of triple drug therapy (cyclosporine, methylprednisolone, azathioprine), complete complement blockade, and absence of an induced primate anti-mouse antibody response [258]; tacrolimus or cyclosporine treatment with additional inductive treatment using prednisolone or mycophenolate mofetil [259]; or local immunosuppression by co-transplantation of liposomal tacrolimus [260].…”