Infection of human neural xenografts

Details Infection of human neural xenografts Infection of human neural xenografts

1992-10-23

2001-10-23

Hauda, Karen M. (Department: 1632)

Multicellular living organisms and unmodified parts thereof and

Nonhuman animal

The nonhuman animal is a model for human disease

C800S003000, C800S018000, C424S009362, C424S093100

Reexamination Certificate

active

06307122

ABSTRACT:

TECHNICAL FIELD
The field of this invention is the use of human neural human xenografts in the eye of an immunocompromised host for studying the effect of various agents on human neural tissue.
BACKGROUND
In the attempts to understand human disease and develop therapies, the medical and associated fields have frequently relied upon analogies to observations in animals. While there are a number of similarities between non-primates and primates, there are also a large number of differences. Many of the naturally-produced agents, such as cytokines, hormones, surface membrane proteins, blood proteins, and the like, differ significantly in their composition. Most importantly, for the transduction of signals, cellular interactions, regeneration and differentiation, the molecules involved frequently have a narrow range of host specificity. Where autocrine or paracrine mechanisms are not involved, xenogeneic tissue introduced into a non-primate host must totally rely upon the host for the source of ligands not produced by the xenogeneic tissue or other xenogeneic tissue must be supplied which makes such ligands available. Furthermore, xenogeneic tissue is subject to rejection by an immunocompetent host, so that means must be provided to protect the xenogeneic tissue from degeneration as a result of immune rejection. There are no viable hosts which have no protective mechanisms against foreign entities.
There has been substantial interest in using immunosuppressive agents or immunocompromised hosts to extend the period in which xenogeneic explants may be maintained as viable functional tissue. Frequently, in order to be useful to study the effect of the agents on the xenogeneic tissue, the tissue must retain most if not substantially all of its natural characteristics. However, since the xenogeneic tissue, at best, is only a very small amount of tissue compared to the entire host, it can be subject to many modifications which may change its characteristics, so as to substantially reduce its predictive capability as to the response of the xenogeneic host.
Where the xenogeneic tissue has mobile cells, such as host organs of peripheral blood lymphocytes, such as lymph nodes, thymus, spleen, pancreas, tonsils and the like, these cells may be rapidly displaced by the xenogeneic host cells. Furthermore, vascularization and lymphatic connection can result in the xenogeneic tissue being invaded by host endothelial cells which provide the vessels. Other host cells may also invade the tissue, so as to change the characteristics of the tissue. It is therefore not sufficient that the tissue remain viable or even grow, it is necessary that the tissue retain a substantial degree of similarity to the native tissue, so as to provide responses which are predictive of the responses of the native tissue in the source host for the xenogeneic tissue.
Humans as a host are particularly unique, in the many restrictions which apply to humans and the manner in which they may be studied. Normally, one cannot induce a disease in a human to study the etiology of the disease. Nor can one treat a human with an agent, without first having gone through extensive tests with other mammals, to determine efficacy and pharmacological properties. With many diseases, there are many infectious agents which are tropic for human tissue. In other pathologic conditions, human tissue may respond quite differently from other hosts, due to the nature of its surface membrane proteins, particularly as to metabolic pathways, pharmacology, and the like.
It is therefore of substantial interest that mammalian hosts, particularly small mammalian hosts, be developed, which allow for the study of the response of human tissue to a variety of agents, particularly pathogenic agents and therapeutic agents used to treat the infection or diseased state.
RELEVANT LITERATURE
van Dooremaal,
Utrechsche Loogeschool
, (1873); 3, 277-290 lodged cells from human-labial mucosum and other rather unlikely explants in the rabbit anterior chamber. Explanted fetal retina, both allo- and xenotrans-plantation, in the study of retinal plasticity in the rat anterior chamber has been reported by del Cerro, M.,
Retinal transplants
. In: Osborne, N., Chader, J., eds,
Progress in Retinal Research
. Vol. 9, Oxford, Pergamon Press, 1989;230-272; Royo and Quay, Growth (1959); 23, 313-336; del Cerro, M., et al., Invest. Ophthalmol.
Vis. Sci
. (1984); 25, 62(abstr.); del Cerro, M., et al. ibid. (1985); 26, 1182-1185; del Cerro, M., et al., Neuroscience (1987); 21, 707-724; and Medawar,
Br. J. Exp. Pathol
. (1984); 29, 58-69. Extensive research has been conducted in the area of syngeneic and xenogeneic grafting of CNS tissue, especially in the study of mechanisms of human brain development. Olson, et al.,
Prog. Brain Res
. (1988); 78, 583-590, grafted several areas of 8-11 week gestation human fetal brain and spinal cord into the anterior chamber of nude mice, nude rats and rats immunosuppressed with cyclosporin A. First trimester human cerebellar and cerebral cortex, and hippocampus and spinal cord xenografts appear to develop histologically according to a human timetable. Anchen, et al.,
Exp. Brain Res
. (1989); 75(2), 317-326; Bickford-Wimer, et al.,
Proc. Natl. Acad. Sci. USA
(1987); 84(16), 5957-5961; and Granholm, et al.,
Exp. Neurol
. (1989); 104, 162-171. Host transplantation survival of first trimester human CNS and retina xenografts have been reported to be as long as 200 days. Aramant, et al.,
Restorat. Neurol. Neuro. Sci
. (1990); 2, 9-22.
Epstein, et al.,
J. Neural Transplantation and Plasticity
(1992); 3, 151-158 report xenografts of second trimester human fetal brain and retinal tissue in the anterior chamber of the eye of immunosuppressed rats. Cvetkovich, et al.,
Proc. Natl. Acad. Sci. USA
(1992); 89, 5162-5166 describe human immunodeficiency virus-type one infection of neural xenografts. The SCID-hu mouse has been reported as a model system for study of HIV-1 infection of human cells. McCune, et al.,
Science
(1988); 241, 1632-1639.
SUMMARY OF THE INVENTION
Methods and non-primate animals are provided for the study of agents on neural tissue and the blood/brain barrier. Human retinal and/or CNS tissue is implanted into the anterior chamber or subretinal space of the eye of an immunocompromised non-primate mammalian host and allowed to become established. The neuronal tissue may then be subjected to a variety of agents by various means depending upon the agent and the tissue observed or removed and analyzed. Of particular interest as agents are disease-causing agents, e.g., pathogens which are tropic for human neural tissue, and the drugs used to treat the pathology.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
In accordance with the subject invention, novel chimeric hosts and their use are provided, where the chimeric hosts are characterized by having xenogeneic viable functional neuronal tissue in at least one eye, being immunocompromised, as a result of an immunosuppressive drug or regimen or a genetic lesion, and wherein said xenogeneic tissue may be subjected to an agent tropic for said xenogeneic tissue but not tropic for said host. Usually, the implant will be normal tissue, but may include diseased tissue.
The implants which are introduced into the eye will normally comprise primate, particularly human, retinal or brain tissue, more particularly fetal tissue, of the first and second trimester, for some applications preferably the second trimester, where the first trimester is up to about 11 weeks, and the second trimester is from about 12-24 weeks, particularly 12-20 weeks.
The brain regions of interest are particularly the telencephalon, including full thickness cortical mantle with ventricular surface or intact retina, or fragments thereof. The brain region comprises neuronal, macroglial and microglial elements. The retina tissue will generally be dissected free of other structures in the eye and may be mechanically or enzymatically dissociated. Normally, the tissue fragments will be from about 0.2-5 mm, more usually from about 0.5-2 mm

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