Immunosuppression of canine renal allograft recipients by CD4 and CD8 monoclonal antibodies

Abstract

A state of tolerance to MHC mismatched allografts can be generated in rodents by treatment with CD4 and CD8 monoclonal antibodies (mAb). In order to transpose this type of therapy to large animals and ultimately to the clinic, a suitable model is required. To this end we have generated a series of mAb to the canine CD4, CD8, and Thy-1 antigens and have tested their ability to prevent rejection of renal allografts. Donor-recipient pairs were selected from a colony of mongrel dogs in which untreated rejection of two haplotype-mismatched kidneys occurred by day 7 (defined as a serum creatinine > 300 mumol/l). Therapy with either the CD4 or the CD8 mAb, using no other immunosuppression, did not prolong graft survival. Depletion of T cells by a Thy-1 mAb prior to surgery only extended graft survival to day 9. However, treating with combinations of mAb up to day 10 (CD4 plus Thy-1; CD4 plus CD8; or CD4 plus CD8 plus Thy-1) prolonged renal allograft function up to 25 days. Combination of the triple mAb therapy with a sub-therapeutic immunosuppressive drug regimen (cyclosporin A plus azathioprine that alone gave a median survival of 15 days) favored survival to a median of 38 days. This protocol also inhibited the antiglobulin response that had curtailed the effects of mAb treatment, opening the way to more extended, and potentially tolerizing, mAb plus drug regimens.

CD 4 and CD 8 monoclonal antibody therapy in canine renal allografts

“…Mongrel dogs were selected on the basis of strong proliferative responses in MLC [6]. In all but one experimental group (group G, see Table l), the donor-recipient combinations were mismatched for both MHC haplotypes.…”

Successful induction of immune tolerance to enzyme replacement therapy in canine mucopolysaccharidosis I

“…The T cell suppressive drugs CsA plus Aza are often used in transplantation studies (19) but have been used rarely in the study of the immune response to soluble proteins (23). The use of CsA may be counterintuitive based on some studies of costimulation blockade that suggest that CsA may prevent tolerance induction (24), but, in this regimen, CsA may play a different role in preventing T cell activation and immune response Canine SC (open circles) was treated with the CsA plus Aza regimen by using ␣-glucosidase as the toleragen and showed no significant immune response (Ͻ1 OD͞ l).…”

“…We initially studied a series of 60-day regimens that combined methods used in canine tissue transplantation models including ITI of antigen, T cell-specific immunosuppressive drugs, and monoclonal antibodies that deplete mature T cells (19) as shown in Table 1. The antibody response was measured by a direct ELISA for antirhIDU IgG antibodies.…”

“…We undertook the development of an antigen-based approach to tolerance for soluble therapeutic proteins that is based on T cell-specific strategies and drugs studied in canine tissue transplantation rather than the B cell-specific drugs usually used for soluble protein tolerance (18)(19)(20). T cell responses fundamentally regulate B cell responses to complex antigens through T cell help and other mechanisms, and we reasoned that mechanisms that alter the T cell response to cell-associated antigens would be more effective at regulating T cell responses to soluble antigens.…”

Crossing the bridge: large animal models in translational transplantation research

“…Indeed, this approach was one of the first to be rigorously investigated with intent on translation to human therapy. Monoclonal antibodies specific for dog CD4, CD8, and thy‐1 have been developed by Waldmann (116) and tested for their ability to both deplete T cells in outbred dogs and prolong renal allograft survival. These agents were most effective when used in combination, but they failed to prolong survival more than a mean of 38 days.…”