Immunomodulation with Intrathymic Grafts or Anti-Lymphocyte Serum Promotes Long-Term Intraspinal Allograft Survival

Abstract

In this study, we sought to test whether introduction of fetal cells into the adult rat thymus would promote immunotolerance to subsequent donor-type allografts in the injured spinal cord. To first evaluate intrathymic survival of fetal central nervous system (CNS) tissue, fragments of E₁₄ Sprague–Dawley (SD) fetal spinal cord (FSC,_SD) were injected into the thymuses of either adult, outbred SD, or Wistar rats. Histological examination revealed well-differentiated grafts in both the SD (10 out of 13) and Wistar (7 out of 13) recipients. We next examined whether prior intrathymic exposure to FSC graft-derived alloantigens leads to enhanced survival of subsequent allografts into the injured, adult spinal cord. Wistar rats thus first received FSC_SD tissue as intrathymic grafts coupled with single-dose, anti-lymphocyte serum (ALS) ablation of the circulating host T-cell population. Ten days later, FCS_SD was transplanted into an aspiration lesion of each intrathymic graft recipient's spinal cord. After 60 days, 87% of two-stage graft recipients (n = 15) exhibited viable intraspinal (IS) grafts compared to 38% (3 out of 8) observed in the controls (i.e., not receiving intrathymic grafts). Another group of Wistar rats that had received ALS (only) at the time of the IS FSC_SD transplant (n = 8) also had 75% graft survival rates after 60 days. These initial findings show that the intrathymic microenvironment can be a compatible ectopic site for fetal SC graft development and survival. Also, the enhanced survival of intraspinal grafts in animals with previous intrathymic implants or ALS administered at the time of grafting suggests the potential for inducing immunoprotection of some fetal neural allografts in adult recipients.