A novel biologic immunomodulator, HDFx, protects against lethal hemorrhage, endotoxins and traumatic injury: potential relevance to emerging diseases.

For more than 125 years, it has been known that the RES, macrophages and the innate immune system play fundamental roles in host defense against pathogenic infections, trauma, hemorrhage, and combined injuries. Some years ago, we and others reported that the RES-macrophage system was intimately connected to resistance to these bodily stressors, among other injuries. We tested the hypothesis that induction of tolerance (either spontaneous, RES-stimulated, or drug-induced) might be associated with production of a yet-to-be-identified biologic host defense factor, which we have termed HDFx. The results presented, herein, demonstrate for the first time that: 1) the MW of this protein, HDFx, is approximately 35-40 KDa , larger than known defensin peptides and much smaller than the larger MW fibronectins and complement products; 2) we describe some of HDFx's physico-chemical characteristics; 3) approximately 80 % of HDFx's plasma biological activity is derived from macrophages; 4) about 15-20 % of its activity is derived from natural killer (NK) cells; 5) polymorphonuclear leukocytes are not a source of HDFx synthesis or release; 6) known stimulants of the RES-macrophage system (i.e., denatured human serum albumin, triolein, and choline chloride) effect phagocytic stimulation of macrophages and protection against endotoxins, trauma, and hemorrhage via synthesis and release of HDFx; 7) adaptation to lethal trauma is dependent on the biological activity of HDFx; and 8) repeated administration of purified HDFx to rats, over several months, does not produce any detectable pathologies. Lastly, the release of cytokines (i.e., IL-2,IL-6,IFN-gamma) from lymphocytes, after hemorrhage and trauma, at least in rodents, appears to be dependent on the available plasma levels of HDFx. Since it is present also in mice, guinea-pigs, and rabbits, we are tempted to speculate that HDFx could prove (if found in humans) to be useful against potential biothreats, new emerging diseases, high -risk surgical procedures, hospital-borne infections, and burn injuries, where the chances for superimposed bacterial infections present great risk.