Surgery – Miscellaneous – Methods
Reexamination Certificate
2002-03-14
2003-12-09
Isabella, David J. (Department: 3738)
Surgery
Miscellaneous
Methods
C435S242000, C623S066100
Reexamination Certificate
active
06659107
ABSTRACT:
TECHNICAL FIELD
The invention relates to the use of low-dose photodynamic therapy to modify donor tissue for xenograft transplantation. More particularly, it relates to exposing donor tissue intended for a recipient of a different species from the donor tissue to a photosensitizer and low intensity light.
BACKGROUND ART
PCT application publication no. WO96/21466 published Jul. 18, 1996, and incorporated herein by reference, describes a method for reducing the rejection of allografts by subjecting the donor tissue intended for an allograft recipient to low-light level photodynamic therapy. Skin allografts subjected to this treatment have enhanced survival times. Additional data demonstrating this effect are also described in U.S. Ser. No. 08/759,318 filed Dec. 2, 1996, and incorporated herein by reference. This work has also been reported by Obochi, M. O. K. et al.,
Transplantation
(1997) 63:810-817.
These applications further mention that, in general, transplantation of tissue or organs is of three general types: syngeneic, where the donor tissue is of the same genotype as the recipient; allogeneic, wherein an allograft is derived from a donor of the same species as the recipient; and xenogeneic, where a xenograft is derived from a donor of a different species from the recipient. Transplantation using xenografts is of particular interest for use in human recipients since nonhuman donors can be used. However, model systems for such xenograft transplants can be constructed using two separate species of any derivations, such as rat/mouse, pig/bovine, and baboon/human.
Photodynamic therapy generally is a technique whereby a photosensitizer is administered directly to a tissue or organ or to a subject and the area desired to be treated is irradiated with light that is absorbed by the photosensitizer. In this state, the photosensitizer exerts an effect on the tissue or cells containing the photosensitizer. The effect may be cytotoxic or, alternatively, there may merely be an alteration in the function of the target cells or tissues. This approach has been used for selectively destroying tumor tissues, atherosclerotic plaques, the lesions of surface skin diseases, and unwanted pathogens in blood. Photodynamic therapy (PDT) has also been used to target activated cells of the immune system selectively.
Various effects of PDT on the immune system have been studied. It has been shown that photodynamic therapy using UV light, in particular 8-methoxypsoralen and UVA radiation, decreases 1 a antigens and the ATPase marker of epidermal Langerhans cells (LC) (Aberer, W. et al.,
J Invest Dermatol
(1981) 76:202). The more standard photodynamic therapy combination of Photofrin® with visible light is able to inhibit APC from stimulating allogeneic cells in the MLR (Gruner, S. et al.,
Scand J Immunol
(1985) 21:267). PDT with UVA light also inhibits upregulation of ICAM-1 expression by Langerhans cells (Tang, D. et al.
J Immunol
(1991) 146:3347). Photodynamic therapy using porphyrins inhibits the high affinity F
c
-receptor on human monocytes (Krutmann, J. et al.,
J Biol Chem
(1989) 264:11407).
Initially, PDT employed fairly high levels of radiation with the absorbed light. However, it has been shown that for certain applications, in particular modulating the immune system, only ambient light is necessary to activate the photosensitizer. Thus, “low-level” PDT is conducted at much lower intensities of irradiation than those required to obtain a recognized photodynamic effect, such as skin erythema. A detailed description of low-dosage PDT and its effect on the immune system is found in PCT application publication no. WO96/22090 published Jul. 25, 1996, and in U.S. Ser. No. 08/856,921 filed May 16, 1997. In general, the radiation levels in “low-dose PDT” have upper limits in the range of 100 mW/cm
2
, more generally about 50 mW/cm
2
or 25 mW/cm
2
and lower intensities of less than 5 mW/cm
2
, preferably less than 1 mW/cm
2
and more preferably less than 500 &mgr;W/cm
2
can also be used. Another criterion for radiation levels in low-dose PDT when an intact subject is administered low-dose PDT is that the light level used is less than one-quarter, preferably less than one-sixth, of that necessary to induce skin erythema in that subject. Still another measure of light dosage relates to total energy applied. Low-dose PDT employs energies of 10 J/cm
2
or less. The above-referenced applications describing treating of donor tissue for allograft transplantation describe the use of low-dose PDT for that purpose.
Xenografts are generally more at risk for rejection than allografts. Success in regard to a protocol that diminishes the immunogenicity of allografts is clearly not predictive of the success of that technique in diminishing the immunogenicity of xenografts to the extent required to ensure acceptance by the recipient. For example, PCT application no. WO97/11653 published Apr. 3, 1997, purports to describe a protocol using standard photodynamic therapy at conventional light dosage levels to treat both allografts and xenografts to enhance their acceptability to recipient subjects. However, this technique is demonstrated to be useful, if at all, only with respect to allografts. The work described employs phthalocyanine, preinjects the donor animals with this drug, applies levels of 5 &mgr;g/ml of the drug after explantation and during irradiation and supplies radiation at 100 mW/cm
2
for a total energy of 100 J/cm
2
. Fluence at this level kills the cells in the graft. The subject tissue is an aortic graft; indeed, the applicants point out that their technique is applicable only to grafts comprising an extracellular matrix and an amorphous ground substance.
It does not appear that the technique described in PCT application no. WO 97/11653 would thus successfully be applied either to xenografts or to graft tissue which comprises cell suspensions per se, such as those ordinarily used to treat Parkinson's Disease. Other techniques known in the art also appear not to be sufficiently precise or successful to permit xenographic transplantation of neural tissue suspensions. Therefore, the source for replacement neural tissue in, for example, human patients with Parkinson's Disease has been human fetal neural tissue.
On a wider scale, there is only limited experience with interspecies transplantation of organs into humans. The shortage of donors for human patients in need of liver, ocular tissue, cardiac tissue, lungs, and the like is well known. To alleviate this shortage, it has been suggested that animals of another species be used as sources for these donor materials. There have been several reports attempting to evaluate the possibility of using nonhuman sources for transplants into the central nervous system. See, for example, Pakzaban, P. et al.,
Neuroscience
(1994) 62:989-1001 which surveys the literature regarding neural xenotransplantation and editorials by Sloan, D. J. et al.
Neuroscience
(1991) 14:341-346, Fishman, P. S.
Neurobiol
(1986) 36:389-391 and in
The Economist
(Mar. 22, 1997):99-101. An additional summary is that by Borlongan, C. V. et al.,
Neurological Res
(1996) 18:297-304.
Fetal pig dopaminergic neurons have been transplanted into 12 patients with Parkinson's; in one of these patients (who subsequently died), these neurons survived for at least 7 months (Deacon, T. et al.,
Nature Medicine
(1997) 3:350-353). Attempts have also been made to modify the subject in whom the donor tissue will be implanted to become more receptive to the implant. For example, Honey, C. R. et al.,
Exp Brain Res
(1991) 85:149-152 treated recipient murine subjects with monoclonal antibody against the murine equivalent of CD-4 (L3T4) and then provided them with rat-derived POA grafts, resulting in longer survival times of the transplants. Cyclosporin-A is a standard method to immunosuppress recipients of xenografts. Pepino, P. et al.,
Eur Surg Res
(1989) 21:105-113 used photochemotherapy and ciclosporin [sic] in recipient baboons of heterotrophic heart grafts f
Honey Christopher Richard
Levy Julia G.
Margaron Philippe Maria Clotaire
Obochi Modestus O. K.
Yip Stephen
Isabella David J.
Morrison & Foerster / LLP
QLT Inc.
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