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Modulation of platelet aggregation in baboons: implications for mixed chimerism in xenotransplantation. II. The effects of cyclophosphamide on pig peripheral blood progenitor cell-induced aggregation.

Abstract：

BACKGROUND:The induction of tolerance to pig antigens in primates may facilitate the development of successful clinical xenotransplantation protocols. The infusion of mobilized porcine peripheral blood leukocytes (PBPCs, comprised of approximately 2% peripheral blood progenitor cells) into splenectomized preconditioned (whole body irradiation (WBI)-based) baboons, intended to induce mixed hematopoietic cell chimerism, however, results in a severe thrombotic microangiopathy (TM) that includes pronounced thrombocytopenia. Previous studies have indicated that the infused PBPCs initiate platelet aggregation, but that the various individual components of the conditioning regimen are not associated with the development of aggregation. We have now investigated the effects of cyclophosphamide (CPP) as an alternative to WBI on platelet aggregation. METHODS:Splenectomized baboons (n=3) were treated with CPP. Blood samples were collected and platelet-rich plasma (PRP) was prepared. Using light transmission aggregometry, the extent of aggregation induced by platelet agonists (thrombin, adenosine diphosphate (ADP), collagen, ristocetin, and arachidonic acid) was determined in vitro. PRP was also prepared from untreated baboons and from baboons receiving CPP, PBPCs were added, and platelet aggregation was measured in the absence of exogenous platelet agonists. RESULTS:CPP markedly inhibited platelet aggregation induced by all standard agonists. In vitro addition of PBPCs to PRP stimulated platelet aggregation in the absence of any agonists. Prior treatment of baboons with CPP, however, inhibited this effect by 55% to 65%. TM was not evident in baboons receiving a conditioning regimen that included CPP instead of WBI. CONCLUSIONS:Aggregation of baboon platelets and TM is directly induced by PBPCs. CPP has direct anti-aggregatory properties and may provide an alternative strategy to WBI in this pig-to-primate model intended to induce mixed hematopoietic cell chimerism.

journal_name

Transplantation

journal_title

Transplantation

authors

Appel JZ 3rd,Alwayn IP,Correa LE,Cooper DK,Robson SC

doi

10.1097/00007890-200110150-00021

subject

Has Abstract

pub_date

2001-10-15 00:00:00

pages

1306-10

issue

eissn

0041-1337

issn

1534-6080

journal_volume

pub_type

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Modulation of platelet aggregation in baboons: implications for mixed chimerism in xenotransplantation. II. The effects of cyclophosphamide on pig peripheral blood progenitor cell-induced aggregation.