Antibody inhibition of the immunoinflammatory cascade

Abstract

w HEN MICROORGANISMS or other foreign antigens violate the barriers of the body, they initiate a plethora of responses that attempt to curtail the invasion. This process of host defense involves a complex immunoinflammatory cascade that can, if left uncontrolled, wreak as much havoc as the inciting event itself. Infection with gram-negative bacteria and the associated release of endotoxin is a prototypic and clinically relevant example of acute activation of the immunoinflammatory cascade. Figure 1 presents a schematic outline of the immunoinflammatory cascade initiated by gram-negative bacterial infection. The emphasis of this review will be on those steps in the cascade that can be inhibited by monoclonal antibodies (MoAbs). Antibodies can act as opsonins and facilitate the clearance of bacteria. Each bacterial species has type-specific antigenic sites. In recent years, studies have concentrated on defining cross-reactive antisera and monoclonals-the J5 story. Release of endotoxin and other bacterial cellular debris, immune complexes, viruses, etc, activate various cellular and humoral host defense systems. These include complement, kinin, and clotting cascades. Pathogens as well as mediators released from the humoral systems act together to activate various leukocytes, including mononuclear phagocytes and granulocytes. These cells release several potent mediators, such as tumor necrosis factor, and express various cell adhesion molecules. The coordinated activation of both the humoral and cellular limbs of the inflammatory cascade results in an effective defense against invasion. In many cases, this response becomes exaggerated, causes tissue damage, and threatens the host. Antibodies recognizing the various mediators and the cells involved in the cascade can attenuate the severity of the inflammatory response. Several of the sites for possible intervention will be discussed below.