Achieving Dominant Transplantationtolerance

Short courses of therapeutic antibodies have been shown to lead to long-term acceptance of foreign grafts in several experimental systems (reviewed in ref. 4). The first examples of peripheral tolerance induced with monoclonal antibodies were reported in 1986.9,10 In these experiments tolerance to foreign immunoglobulins was achieved after a short-term treatment with depleting anti-CD4 antibodies. It was soon demonstrated that depletion of CD4+ cells was not required for tolerance induction, as similar results were found using F(ab')2 fragments,11-13 non-depleting isotypes5 or non-depleting doses of synergistic pairs of anti-CD4 antibodies.14 Treatment with anti-CD4 antibodies was also shown to lead to long-term acceptance of skin grafts differing by "multiple-minor" antigens5 even in pre-sensitised recipients.15 The same results were also demonstrated for heart grafts across MHC barriers16,17 or concordant xenografts.16

Further demonstrations of transplantation tolerance were later reported with anti-LFA-1 antibodies, alone13 or in combination with anti-ICAM-118 and also with anti-CD2 and anti-CD3 antibodies.19

More recently, co-stimulation blockade of CD28,20 CD40L (CD154)21 or both in combination22 has been shown effective. These findings have recently been extended to non-human primates. In one study, long-term survival of renal allografts was achieved following blockade of CD40L alone.23 Another group achieved pro-

Tolerant mouse (Fig.1 protocol} Receives fresh graft

Receives lymphocytes from non-tolerant mice

Graft accepted!

Tolerant mouse

Grafts rejected

Receives fresh graft T cells are depleted

Receives lymphocytes from non-tolerant mice

Figure E1.2. Demonstration of dominant tolerance. This requires the demonstration of tolerance being imposed on cells with the ability to reject a graft in the absence of regulatory cells.

longed islet allograft acceptance after a similar treatment.24 Interestingly, the association of tacrolimus or steroids to the therapeutic regime abrogated tolerance.23

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