ANTI-CD154 OR CTLA4Ig OBVIATES THE NEED FOR THYMIC IRRADIATION IN A NON-MYELOABLATIVE CONDITIONING REGIMEN FOR THE INDUCTION OF MIXED HEMATOPOIETIC CHIMERISM AND TOLERANCE1

Abstract

One injection of anti-CD154 or CTLA4Ig overcomes the need for TI or prolonged host TCD in a preclinical model for the induction of mixed chimerism and deletional tolerance and thus further decreases the toxicity of this protocol. Achievement of tolerance with conditioning given over 24 hr suggests applicability to cadaveric organ transplantation.

CD4 T Cell-Mediated Alloresistance to Fully MHC-Mismatched Allogeneic Bone Marrow Engraftment Is Dependent on CD40-CD40 Ligand Interactions, and Lasting T Cell Tolerance Is Induced by Bone Marrow Transplantation with Initial Blockade of this Pathway

“…The two long-term chimeras that were prepared with 3 Gy TBI and MR1 alone also showed donor-specific unresponsiveness in MLR and CML, as well as marrow, spleen, and thymic chimerism at the time of sacrifice (34 wk) (data not shown). Thus, lasting chimerism and systemic donor-specific tolerance was reliably induced across a full MHC barrier in chimeras prepared with an incompletely depleting dose of TCD plus MR1, similar to results seen in other mixed chimeras (10). Although similar results were obtained in a minority of mice receiving MR1 without TCD mAbs, MR1 alone did not reliably allow this outcome to be achieved.…”

“…In previous studies, we showed that costimulatory blockade with one injection of anti-CD40L or of CTLA4Ig obviates the need for thymic irradiation or repeated administration of TCD mAbs to overcome intrathymic alloresistance in mice receiving one injection of depleting anti-CD4 and anti-CD8 mAbs (10). The current demonstration that anti-CD4 mAb is not required to achieve such results (i.e., that anti-CD40L and anti-CD8 mAb alone are sufficient to allow the reliable induction of durable mixed chimerism and transplantation tolerance) is of considerable clinical relevance.…”

“…However, this approach had the disadvantage of being associated with prolonged T cell depletion in the recipient, a state that is not desirable in adult humans, in whom limited thymic reserve might greatly delay the recovery of a functional immune system. More recently, we observed that the requirement for either thymic irradiation or repeated T cell-depleting (TCD) mAb injection could be obviated by treating recipient mice with one injection of either anti-CD40 ligand (CD40L) mAb on day 0 or with an injection of CTLA4Ig on day 2 (10). Furthermore, the use of a combination of both of these costimulatory blockers, each given once, completely replaced the requirement for recipient T cell depletion with mAbs and for thymic irradiation (11).…”

“…We have previously demonstrated that treatment of B6 mice with depleting doses of anti-CD4 mAb GK1.5 (1.76 mg) and anti-CD8 mAb 2.43 (1.4 mg) on day Ϫ1, in combination with anti-CD40L mAb MR1 on day 0 and 3 Gy TBI on day 0, allowed engraftment of B10.A fully MHC-mismatched marrow and acceptance of donor skin grafted in the peritransplant period (10). Because complete peripheral T cell depletion is more difficult to achieve in large animals and humans than in mice, we wished to determine whether a similar outcome could be achieved if less than fully depleting doses of anti-CD4 and anti-CD8 mAbs were given in this regimen.…”

Long-Term Control of Alloreactive B Cell Responses by the Suppression of T Cell Help

“…However, relatively little is known of factors that control B cell responses following allograft tolerance induction. Indeed, most investigations of the induction of allograft tolerance have focused on the regulation of T cell responses (1)(2)(3)(4). We hypothesize that control of B cell responses is necessary for stable long-term allograft survival.…”