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Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher's disease - PubMed

  • ️Fri Jan 01 1993

Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher's disease

T E Starzl et al. N Engl J Med. 1993.

Abstract

Background: Liver transplantation for type IV glycogen storage disease (branching-enzyme deficiency) results in the resorption of extrahepatic deposits of amylopectin, but the mechanism of resorption is not known.

Methods: We studied two patients with type IV glycogen storage disease 37 and 91 months after liver transplantation and a third patient with lysosomal glucocerebrosidase deficiency (type 1 Gaucher's disease), in whom tissue glucocerebroside deposition had decreased 26 months after liver replacement, to determine whether the migration of cells from the allograft (microchimerism) could explain the improved metabolism of enzyme-deficient tissues in the recipient. Samples of blood and biopsy specimens of the skin, lymph nodes, heart, bone marrow, or intestine were examined immunocytochemically with the use of donor-specific monoclonal anti-HLA antibodies and the polymerase chain reaction, with preliminary amplification specific to donor alleles of the gene for the beta chain of HLA-DR molecules, followed by hybridization with allele-specific oligonucleotide probes.

Results: Histopathological examination revealed that the cardiac deposits of amylopectin in the patients with glycogen storage disease and the lymph-node deposits of glucocerebroside in the patient with Gaucher's disease were dramatically reduced after transplantation. Immunocytochemical analysis showed cells containing the HLA phenotypes of the donor in the heart and skin of the patients with glycogen storage disease and in the lymph nodes, but not the skin, of the patient with Gaucher's disease. Polymerase-chain-reaction analysis demonstrated donor HLA-DR DNA in the heart of both patients with glycogen storage disease, in the skin of one of them, and in the skin, intestine, blood, and bone marrow of the patient with Gaucher's disease.

Conclusions: Systemic microchimerism occurs after liver allotransplantation and can ameliorate pancellular enzyme deficiencies.

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Figures

Figure 1
Figure 1. Endomyocardial Tissue from Patient 2, with Type IV Glycogen Storage Disease

Panel A, a photomicrograph of a specimen obtained at biopsy in April 1989, three weeks after liver transplantation, reveals diffuse amylopectin deposition (dark red) in the myocytes (PAS-D with formalin fixation, x250). In Panel B, a specimen obtained in April 1992, there are only traces of amylopectin (arrow) (PAS-D with formalin fixation of frozen tissue, x250).

Figure 2
Figure 2. Sections of Lymph Nodes from Patient 3, with Type 1 Gaucher’s Disease

Before transplantation (Panel A), a hepatic hilar lymph node resected with the diseased liver in April 1990 shows marked architectural distortion because of massive deposition of glucocerebroside in Gaucher’s cells (PAS, x50). After transplantation (Panel B), an inguinal lymph node resected in 1992 for analysis of chimerism shows restoration of the architecture, with occasional Gaucher’s cells in the sinusoids (PAS, x50).

Figure 3
Figure 3. Immunocytochemical Analysis of Heart, Transplanted Liver, and Native Liver in Patient 1, with Type IV Glycogen Storage Disease

In Panel A, green fluorescence identifies cells with the donor’s phenotype (HLA-DR1,4; arrows) in the interstitium of the heart (x1000). Panel B shows positive green-staining cells (HLA-DR1,4) in the transplanted liver (x400). Panel C (negative control) shows the absence of donor (HLA-DR1,4–positive) cells in the recipient’s native liver (x400). All sections were stained with a single monoclonal antibody specific for HLA-DR1 and DR4. The yellow globules are autofluorescent intracellular pigment.

Figure 4
Figure 4. Demonstration of Donor DNA after Transplantation in Patient 3, with Type 1 Gaucher’s Disease

Genomic DNA was extracted from the recipient’s tissues and amplified with HLA-DR beta-chain “generic” oligonucleotide primers to determine the subgroup of the donor’s alleles. “Specific” primers were then used to amplify the alleles selectively. The alleles were identified by hybridizing the amplified DNA to radiolabeled allele-specific probes. After HLA-DR1–specific amplification of DNA from the liver, blood, bone marrow, skin, and small bowel, the DNA was separated by electrophoresis on an agarose gel and then analyzed by Southern blotting. The denatured DNA present on the nylon membrane was hybridized to a labeled HLA-DR1 (donor)–specific oligonucleotide probe. For liver DNA, the quantity analyzed was reduced to 1 percent of the other samples. Although lower in intensity, the signal from donor DNA in the small bowel was clearly positive in the original film, although this can be seen only faintly. The negative control was a reaction run without DNA (last lane).

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References

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