Kanchan Rao

Degeneration of optic axons induces the expression of major histocompatibility antigens

Eye removal from adult rats causes induction of major histocompatibility complex (MHC) antigen expression by cells within areas of optic terminal degeneration. Class I MHC antigen expression occurs through the degenerating optic terminal areas, while class II MHC antigen expression is found within areas of degenerating myelinated axons. This could be an important step in the process of immunological recognition and subsequent rejection of neural transplants that are located in the region of the degenerating fibers. It could also be a precipitating factor in certain neurodegenerative diseases of the central nervous system.

The role of MHC and non-MHC antigens in the rejection of intracerebral allogeneic neural grafts

Embryonic DA retinal allografts that have survived for prolonged periods after having been transplanted into the brains of neonatal BN rats can be induced to reject following peripheral sensitization with a DA skin graft. The results show that histocompatibility antigens play the major role in the rejection of grafts placed in the CNS and that a disparity between the retinal and skin grafts for MHC antigens induces a more severe rejection response than does a non-MHC antigen disparity.

Chapter 15 MHC antigen expression in spontaneous and induced rejection of neural xenografts

Publisher Summary This chapter examines the effect of various host immune factors on graft rejection using a xenogeneic neonatal transplant protocol in which graft survival in the vast majority of animals (80 percent) occurs for a prolonged period without rejection. In the chapter, the relationship between major histocompatibilty (MHC) antigen expression and graft rejection seen in spontaneously rejecting xenografts is compared to the patterns found after rejection induced by the following stimuli: (1) systemic sensitization by skin grafting, (2) inducing a local degenerative response by removing the host eye contralateral to the side of the neural implant, and (3) disrupting the blood–brain barrier (BBB) with intra-arterial hyperosmolar mannitol. For all experiments described in the chapter, donor tissue was obtained from E13-14 CD-1 mouse embryos. The eyes were harvested and the retinae were dissected free from the investing layers in ice-cold Hams F-10 medium (Gibco Laboratories). Tissue was transplanted in 1 μl of F-10 medium into the mesencephalon or cerebral cortex of anesthetized P1 Sprague–Dawley rats.

Differential expression of class I and class II major histocompatibility complex antigen in early postnatal rats

Cells expressing major histocompatibility complex (MHC) antigens are rarely found in normal mature brains, but cells resembling microglia can be induced to express these antigens following the onset of neural degeneration. In young rats, these cells show spontaneous expression of class I MHC antigens, which is further enhanced in the superior colliculus by the degeneration resulting from eye removal. By contrast, class II MHC antigen expression does not occur spontaneously and can only be induced by eye removal when the lesion is performed after the first postnatal week, when the optic tract begins to myelinate. We suggest that different signals are responsible for induction of class I and of class II MHC antigen expression.

MHC antigen expression and cellular response in spontaneous and induced rejection of intracerebral neural xenografts in neonatal rats.

Fetal mouse retinae transplanted to the mesencephalon of neonatal rats generally survive for prolonged periods of time without immune suppression suggesting that such grafts enjoy a degree of immunological privilege. A small, but consistent percentage of these transplants, however, ultimately undergo spontaneous rejection. In addition, rejection can be induced by (1) systemically sensitizing the host to the donor antigens by placing a mouse skin graft or (2) producing a local degenerative process adjacent to the graft by removing the host eye contralateral to the side of the retinal transplant. To elucidate the immunological events that underly spontaneous and induced rejection in this system, we examined the distribution of lymphocytes, astrocytes, microglia, and cells expressing major histocompatibility complex (MHC) antigens in unrejected grafts, in transplants showing spontaneous rejection, and in grafts undergoing induced rejection. In unrejected grafts, increased astrocytic and microglial staining was seen around the photoreceptor layer of the graft and at the graft-host interface, but no lymphocytes and only occasional cells expressing MHC antigens were detected. In contrast, spontaneously rejecting grafts showed widespread MHC, lymphocytic, astrocytic, and microglial immunoreactivity that extended well beyond the limits of the transplant into the surrounding host brain. Skin graft-induced rejection produced a temporally consistent, comparatively localized enhancement of astrocytic, microglial and MHC immunoreactivity and infiltration of lymphocytes. Four to five days after skin grafting, before neural graft rejection was detectable histologically, MHC immunoreactivity was demonstrated within the transplant coinciding with the presence of small numbers of lymphocytes and an increase in microglial staining. By 8 days, grafts had undergone profound necrosis. Intense astrocytosis, microglial staining, MHC immunoreactivity, and perivascular lymphocytic cuffing were present within the graft and at the graft-host interface. With longer survival times, several of these changes were also detected within the visual pathways, suggesting that the regions to which the graft projected were also involved, though in a delayed fashion. After eye removal, the temporal pattern of rejection was more protracted and considerably less uniform than that seen after skin grafting. At 7 days, prominent microglial, astrocytic, and MHC immunoreactivity was seen in the area of distribution of the host optic axons within the superior colliculus and to a lesser extent around the graft itself, however, no infiltration of lymphocytes was detected. With longer survival times, an increasing percentage of grafts showed signs of overt rejection with perivascular cuffing by lymphocytes; however, even at 21 days, a small number of grafts remained free of lymphocytic infiltration, despite the presence of intense MHC, astrocytic, and microglial staining. We conclude that the different rejection models studied may involve fundamentally different triggers of the host immune system, but that in each case MHC expression may be the precedent step to graft rejection.

Chapter 35 Immunological implications of xenogeneic and allogeneic transplantation to neonatal rats

Publisher Summary In neonatal hosts, graft rejection can occur both spontaneously and because of specific challenges. This chapter discusses the circumstances associated with graft destruction, particularly with regard to the mechanisms by which it may be precipitated. The chapter also addresses and attempts to answer certain issues, such as how do grafts integrate with the host central nervous system, can transplants placed in the brains of neonatal rats escape recognition by the host immune system, or how do the circumstances associated with neural graft rejection relate to the concept of immune privilege of the brain. While the detailed possible induction of MHC expression as a primary stimulus to graft rejection is yet to be examined, there is evidence available from other experiments, and from the skin allograft studies, to indicate that MHC mechanisms are involved. While, a clear picture of a single graft rejection mechanism has not emerged yet, new experiments suggest a pattern of events. Essentially, the grafts exist in a metastable immune balance that can be disrupted by a variety of factors. However, each one on its own may not be sufficient to provoke a rejection response, but once a critical threshold is reached, a cascade of events may occur which precipitates a classical immune response.