Polyethylene glycol–coated red blood cells fail to bind glycophorin A–specific antibodies and are impervious to invasion by the Plasmodium falciparum malaria parasite

Abstract

IntroductionThe red blood cell (RBC) membrane is architecturally complex and is characterized by significant biochemical diversity. Protein-, lipoprotein-, glycoprotein-, and carbohydrate-rich structures play an important role in ensuring the physical integrity of the cell and carrying out its physiologic functions. 1 However, the presence of these diverse RBC-surface molecules can also have adverse consequences. Several of these structures carry defined polymorphic epitopes, recognized serologically as blood group antigens, which can stimulate alloimmune responses (alloimmunization) after red blood cell transfusion or pregnancy. A second exposure to the same antigen may lead to serious clinical consequences, including hemolytic transfusion reactions and hemolytic disease of the newborn. Alloimmunization is particularly problematic in patient groups who receive multiple transfusions. For example, up to 30% of chronically transfused patients with sickle cell disease become sensitized to one or more blood group antigens. 2 Aside from alloimmunization, a more recently recognized consequence of the presence of diverse molecules on the surface of RBCs is that microorganisms have adapted to use certain ones as "docking points" in the initiation of disease. As an example, parvovirus B19 (a prominent cause of pure red cell aplasia) homes to erythroid precursors in the marrow through an interaction with the P blood group antigen. 3 In addition, the Duffy and glycophorin A blood group glycoproteins have been shown to play important roles as receptors for human malaria parasites. 4 Plasmodium vivax has an absolute requirement for a Duffy protein interaction in order to successfully invade and parasitize human RBCs. Consequently, red cells of the Fy aϪbϪ phenotype are resistant to invasion. 5 Plasmodium falciparum malaria parasites use glycophorin A epitopes to achieve the efficient invasion of RBCs. 6 The essential biochemistry of the complex invasion process of this parasite is not as well understood as that for P vivax. However, the gene encoding an important glycophorin A binding ligand of P falciparum, EBA-175, has been cloned and is being intensively studied. [7][8][9] There are circumstances in which it would be desirable to remove some of the antigenic epitopes or potential binding sites from the RBC surface, either to prevent alloimmunization or make RBCs resistant to microbial attack. Enzymatic removal of specific protein or carbohydrate structures is one possible approach. By using a specific exoglycosidase, this technique has been used successfully to cleave the B blood group antigen, allowing for the conversion of group B RBCs to group O before transfusion. 10,11 However, this general approach is limited by the availability of enzymes of the required specificities. Of the more than 200 known blood group antigens, B is the only antigen that has been specifically and effectively removed enzymatically. Although other less-specific proteases and glycosidases will certainly remove many antigens, they will also compr...

Conjugation of methoxypolyethylene glycol to the surface of bovine red blood cells

“…Research has been ongoing to test the feasibility of modifying the entire surface of hRBCs to produce an immunologically silent RBC by either removing surface antigens or hiding them to prevent antibody binding (Blackall et al, 2001;Scott, 1997a). Unfortunately, removing surface antigens by enzymatic cleavage has been shown to compromise the RBC's structural and functional integrity (Blackall et al, 2001).…”

“…Unfortunately, removing surface antigens by enzymatic cleavage has been shown to compromise the RBC's structural and functional integrity (Blackall et al, 2001). Coating the RBC membrane to hide surface antigens is one potential strategy to preserve the structural integrity of the RBC.…”

Frequencies of Blood Group Systems MNS, Diego, and Duffy and Clinical Phases of Carrion’s Disease in Amazonas, Peru

“…All of these proteins are present in the erythrocyte membranes and are involved in the entrance of pathogens like Plasmodium . Homozygous defective mutations for these proteins have been reported as being protective for malarial infection in Africa and Asia [19]. Very little information is available from South American populations but some studies in Brazil and Colombia have confirmed that Duffy, MN, and Ss variant blood groups are resistant to P. falciparum infection in some populations [20–22], although this concerns the protozoan, studies in bacteria such as B. bacilliformis are currently underway.…”

Simultaneous Camouflage of Major and Minor Antigens on Red Blood Cell Surface With Activated mPEGs

“…The chronically transfused patients, who suffer from thalassemia and sickle cell disease encounter the problems of alloimmunization (6,7). Immunoprotection of RBCs can be achieved by covalent attachment of methoxy polyethylene glycol (mPEG) to the proteins expressed on the cell membrane (PEGylation) (8,9).…”