Selective plasmapheresis in dogs for delay of heterograft response.

Abstract

Selective plasmapheresis is a technique whereby a gamma globulin rich fraction is electrophoretically separated from heparinized whole blood maintained in extracorporeal circulation(1–3). The general procedure is similar to that employed with artificial kidneys and, more specifically, with blood electrodialysis(4). It employs the forced-flow electrophoretic technique(1,2,5,6), which has been recently employed for the preparation of anti-lymphocytic globulins from horses in vivo(7) and in vitro(8,9). In the present series of experiments it has been applied to the experimental modification of the rejection reaction of pig kidney's xenografts in dogs. These experiments have been prompted by the urgent need for a method for removal of antibodies in previously immunized patients to allow kidney transplantation. While the central role of small lymphocytes in chronic rejection has been known a long time, the more dramatic effect of preformed circulating antibodies in causing hyperacute rejection has been recognized only recently. Kissmeyer-Nielsen, et al. (10) described hyperacute rejection mediated by IgG, IgA, and IgM antibodies to renal allografts in 2 patients. The microscopic picture of these grafts revealed cortical necrosis caused by microthrombi in the glomeruli and small arterioles similar to the picture produced by the Schwartzman reaction. Since that report, clinical and experimental evidence of antibody mediated rejection of renal allografts has been described by Williams, Starzl, Clark, Najarian and others(11–17). Patients exhibiting this response are believed to have become immunized during multiple pregnancies, by means of repeated blood transfusions while awaiting renal transplantation, or by previous renal transplants. The reaction appears to be complement dependent. It is possible to detect these antibodies by means of a crossmatch with donor leukocytes, thus patients subject to hyperacute rejection can be identified. A similar mechanism is believed to be responsible for the rapid rejection observed in xenografts(15–17). The pig kidney-dog recipient model chosen in the present work is an example of the most acute type of rejection known, the transplanted kidney failing without exception within 6–15 min.(18–20). In 2 dogs treated by selective plasmapheresis, the pig kidney was found to survive approximately 2 hr. with moderate urine output. A third dog retained the pig's kidney for 3 hr., with copious urine output. This significant delay in the rejection is probably attributable to the depletion of circulating antibodies. If so, it would mark the first modification of an immune reaction by the removal of circulating antibodies by purely physical means. Other approaches to the problem of removal of preformed antibodies(21,22) include adsorption of circulating antibodies from the host by means of donor tissue, depleting the host of complement, and depleting the host of globulin. Adsorption techniques have been accomplished both in experimental and in clinical renal transplants in immunized recipients with some success. However, present adsorption techniques deplete the host of platelets and result in a bleeding diathesis all too frequently.