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Contribution of monocyte-macrophage system to serum alpha 1-antitrypsin
W Krivit1, J Miller, M Nowicki
1Department of Pediatrics, Variety Club Children's Hospital, University of Minnesota, Minneapolis.
Insights
This study investigated the role of monocyte-macrophage systems in producing alpha 1-antitrypsin (A1AT). Results indicate that the donor monocyte-macrophage system does not significantly contribute to serum A1AT levels after bone marrow transplantation.
Area of Science:
- Immunology
- Genetics
- Biochemistry
Background:
- Alpha 1-antitrypsin (A1AT) is a major serum antiprotease.
- A1AT deficiency is linked to infantile cirrhosis and emphysema.
- A1AT is primarily synthesized by the liver but also found in monocytes/macrophages in vitro.
Purpose of the Study:
- To quantitatively and qualitatively assess the in vivo contribution of the monocyte-macrophage system to serum A1AT.
- To determine if donor-derived monocyte-macrophages produce serum A1AT after bone marrow transplantation.
Main Methods:
- Bone marrow transplantation (BMT) was used to replace the recipient's monocyte-macrophage system with donor origin.
- Protease inhibitor (Pi) typing was performed on recipients and donors.
- Sensitive silver stain methods were used to detect A1AT variants (S and M2 bands).
Main Results:
- Eleven recipient-donor pairs with distinct Pi types were studied.
- In six long-term survivors, donor A1AT variants (S or M2) were not detected in recipient serum.
- Sensitive staining methods could detect low percentages of A1AT variants in vitro but not in vivo post-BMT.
Conclusions:
- The study found no detectable contribution of the donor monocyte-macrophage system to serum A1AT levels in vivo after BMT.
- These findings suggest that the liver is the predominant source of serum A1AT.
Abstract:
The major serum antiprotease is alpha 1-antitrypsin (A1AT). Deficiency of A1AT can result in infantile cirrhosis and premature emphysema, both of which have a high degree of morbidity and significant mortality. Although synthesized primarily by the liver, A1AT has been histochemically localized in monocytes and macrophages in vitro and has been shown to be produced in tissue culture of monocyte-macrophage origin. This study was planned to quantitatively and qualitatively assess the in vivo monocyte-macrophage system contribution to serum A1AT. We used bone marrow transplantation (BMT) as an experimental method because there is commanding evidence that after engraftment, the monocyte-macrophage system of the recipient is replaced by that of donor origin. Protease inhibitor (Pi) typing was done on 150 potential BMT recipients and on their potential donors before transplantation. From these initial recipients, 92 eventually underwent transplantation, and 11 recipient-donor pairs, in which each donor's Pi type contained a band not in the recipient's Pi type, were chosen for the study. Six recipients survived beyond 100 days after BMT, and in these cases the donor contained either an S or an M2 band in his or her Pi type not present in the recipient. Using a silver stain method on diluted serum of known M1M2 and MS types, we were able to detect a 2% dilution of the S band and a 25% dilution of the M2 band. When the same method was applied to gels used in typing recipient Pi after BMT, we were unable to detect any contribution to serum A1AT by the donor monocyte-macrophage system.