Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
1998-03-12
2001-03-13
Casler, Brian L. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C250S461200, C600S477000
Reexamination Certificate
active
06201989
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to methods of detecting the possible rejection of transplanted tissue, such as a transplanted organ. The present invention also relates to apparatus for detecting such rejection, and methods relating to such apparatus.
BACKGROUND OF THE INVENTION
The transplanting of tissues such as organs is a well recognized technique in surgery. Unfortunately, a major, long-standing difficulty is the rejection of the transplanted tissue by the host. Briefly, the immune system of the host recognizes a foreign body (i.e., the transplanted tissue) and then rejects that foreign body. A variety of techniques exist for the suppression of rejection, and improved rates of success are now being achieved. A popular technique is to suppress the recipient's immune system, for example with cyclosporin. However, such immunosuppression techniques carry risks for the patient, and are therefore minimized, when possible, by attempting to determine prior to immunosuppression if the tissue exhibits characteristics of rejection.
A standard means of determining whether an organ is being rejected is the conduction of physical biopsies (such as an endomyocardial biopsy (EMB) for the heart). In the case of heart transplants, accurate diagnosis is vital for the effective care of the heart transplant, and percutaneous transvenous EMB is a standard method for such assessment of rejection. Crudely described, this means inserting a catheter comprising a device known as a bioptome, which comprises a wire with tiny jaws at the distal end, into a blood vessel. Many varieties of catheters and bioptomes are known in the art. See, e.g., U.S. Pat. No. 3,964,468; U.S. Pat. No. 4,953,559; U. S. Pat. No. 4,884,567; U.S. Pat. No. 5,287,857; U.S. Pat. No. 5,406,959; WO 96/35374; WO 96/35382; WO 96/29936; WO 96/35374. The distal end of the catheter is fed into an entry point, typically on the leg or neck, and then on to the heart chamber where a tiny piece of tissue is clamped in the jaws of the bioptome and removed for analysis.
This biopsy permits accurate detection of the presence and the severity of histologic changes in the transplanted tissue once the site of rejection is found. In particular, the heart material obtained from the biopsy is graded for the level or severity of the rejection. The International Society for Heart and Lung Transplantation (ISHLT), Kolbeck et al.,
Transplant Pathology,
p. 200 (Am. Soc. Clin. Path., 1994), rates cardiac rejection as follows:
TABLE 2
International Society for Heart and Lung Transplantation
Grade 0
No evidence of acute rejection
Grade 1
Mild
A. Focal/Perivascular
B. Diffuse/Interstitial
Grade 2
Moderate, Uni-focal
Grade 3
Moderate, Multi-focal
A. Several foci
B. Diffuse
Grade 4
Severe
Ongoing
Mild, moderate, severe
Resolving
In an alternative formulation, Billingham's Histopathologic Classification of Rejection, Kolbeck et al.,
Transplant Pathology,
p. 199 (Am. Soc. Clin. Path., 1994), establishes the features of tissue rejection as follows:
TABLE 3
Billingham's Histopathologic Classification of Acute
Rejection in Human Heart Allograft
Severity of Acute
Prognostic and
Rejection
Features
Implications Therapeutic
Mild
Rare (usually 1-2) localized
Reversible, typically
perivascular collections of
without augmentation of
mononuclear cells with limited
immunosuppressive
extension into the interstitium.
therapy.
No definite myocardial injury.
Moderate
Collection of “activated”
Reversible, typically with
perivascular and interstitial
augmentation of therapy
mononuclear cells with associated
and rebiopsy.
myocyte injury.
Severe
Widespread inflammatory
Reversible, but with
infiltrates including mononuclear
difficulty. Requires
cells and often polymorphonuclear
augmentation of therapy.
leukocytes and eosinophils.
Multifocal tissue and small vessel
necrosis is associated with fresh
hemorrhage.
Resolving
Granulation tissue at various
Reversed rejection,
stages if collagenization. Includes
spontaneously or
numerous fibroblasts with
therapeutically induced.
scattered mononuclear cells,
plasma cells and phagocytosed
lipochrome pigment.
A patient may require an average of 5 and as many as 10 biopsies per biopsy procedure. Thus, over the first year of a heart transplant recipient, as many as 180 EMBs are taken. A typical schedule for EMBs is as follows:
TABLE 1
Right Ventricular Biopsy Protocol for Heart Transplant
Period
Time
Frequency
Procedures
Immediate post-
0-4 weeks
from day five,
6
operative
twice weekly
4-6 weeks
weekly
3
Late post-operative
2-3 months
bimonthly
4
4-6 months
monthly
3
6-12 months
quarterly
2
Total
First Year
18
After one year
yearly
(in the absence of
rejection)
After rejection
14-21 days
therapy
EMBs, and other biopsies, are problematic, however, because during each biopsy a number of potential complications may occur. These complications include the following:
right ventricular perforation
cardiac tamponade
ventricular and supraventricular arrhythmia
embolus (thrombus or air)
pneumothorax air in the pleural cavity
infection
bleeding
EMBs are the principle method for monitoring cardiac allograft rejections.
Thus, the EMB, which is a physical biopsy and diagnostic aid, is hazardous for the patient. Attempts have been made to reduce the number of biopsies per patient, but these attempts have not been successful, due in part to the difficulty in pinpointing the sites where rejection starts and to the difficulty in assessing tissue without performing the actual biopsy.
Accordingly, there has gone unmet a need for methods and apparatus that reduce the number of EMBs that a patient must suffer subsequent to undergoing a transplant procedure. There has also gone unmet a need for methods and devices that assist in pinpointing sites where rejection starts. The present invention provides these and other related advantages.
SUMMARY OF THE INVENTION
The present invention provides methods of, and apparatus for, detecting the possible rejection of transplanted tissue, such as a heart, by a host. Generally, the methods comprise subjecting the tissue to ultraviolet to visible light illumination, collecting the fluorescence light induced by the illumination to permit analysis, and comparing the results from the transplanted tissue to results for known tissue, typically healthy tissue; the fluorescence from tissue having characteristics of rejection is different from the fluorescence from healthy tissue.
Accordingly, in one aspect the present invention provides methods for determining whether a transplanted tissue comprises one or more characteristics indicative of rejection by a host. The methods comprise a) illuminating the transplanted tissue under conditions suitable to cause the transplanted tissue to fluoresce; b) collecting the fluorescence to provide a transplant fluorescent signature; and c) comparing the transplant fluorescent signature with a known fluorescent signature representative of the same type of tissue as the transplanted tissue, and therefrom determining whether the transplanted tissue exhibits one or more characteristics indicative of rejection.
In a preferred embodiment that relates to this and other aspects of the present invention (which is so for other preferred embodiments unless a given aspect of the invention indicates that such embodiment does not apply to that aspect), the transplanted tissue is illuminated with light that does not comprise UV light, further preferable light that consists essentially of blue light, even further preferably light that consists essentially of a wavelength of about 442 nm.
In another preferred embodiment, methods are implemented using a catheter or endoscope that comprises at least one illumination light guide that conducts light to the transplanted tissue to illuminate the transplanted tissue and at least one collection light guide that collects fluorescence from the transplanted tissue, and the methods further comprise collecting a plurality of transplant fluorescence signatures preferably without substantially moving the catheter or endoscope r
MacAulay Calum E.
MacKinnon Nicholas B.
McManus Bruce M.
Thompson Christopher R.
Whitehead Peter D.
Biomax Technologies Inc.
Casler Brian L.
Graybeal Jackson Haley LLP
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