Prevention of kidney allograft rejection using anti-CD40 and anti-CD86 in primates

Haanstra, Krista G.; Ringers, J.; Sick, Ella A.; Ramdien-Murli, Seema; Kuhn, Eva-Maria; Boon, Louis; Jonker, Margreet

doi:10.1097/01.tp.0000054835.58014.c2

Cited by 120 publications

(111 citation statements)

References 29 publications

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“…The striking inability of PG102-mediated CD40 engagement to trigger early signaling pathways in immune cells is consistent with its reported inhibition of CD40-mediated B cell effector functions (10,11). This also correlates with PG102-mediated inhibition of in vivo CD40-dependent promotion of inflammation and transplant rejection in animal models (12)(13)(14) and early clinical human studies (15). In some regards, this PG102-induced altered CD40 signaling resembles the "alternative" signaling pathways that bacterial superantigens are reported to trigger when they bind TCR/MHC complexes (reviewed in Ref.…”

Section: Discussionsupporting

confidence: 80%

“…Subsequently, a chimeric form of 5D12 (ch5D12) containing human IgG4 constant regions was produced. The ch5D12 mAb prevents development of experimental autoimmune encephalomyelitis in marmosets (12), as well as prolongs the survival of kidney allografts and allows repeated systemic administration of adenoviral gene therapy vectors in rhesus monkeys (13,14). In an open-label dose-escalation phase I/IIa study of Crohn's disease patients, ch5D12 was well tolerated and showed promising clinical benefit (15).…”

mentioning

confidence: 99%

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Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Bankert

Oxley

Smith

et al. 2015

The Journal of Immunology

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Blocking the interaction of CD40 with its ligand CD154 is a desirable goal of therapies for preventing and/or ameliorating autoimmune diseases and transplant rejection. CD154-blocking mAbs used in human clinical trials resulted in unanticipated vascular complications, leading to heightened interest in the therapeutic potential of antagonist mAbs specific for human CD40. Abs that do not require physical competition with CD154 to inhibit CD40 signaling have particular therapeutic promise. In this study, we demonstrate that the antagonist anti-human CD40 mAb PG102 fails to trigger CD40-mediated activation, as well as impairs CD154-mediated CD40 activation, via a distinct nonstimulatory CD40 signaling mechanism. PG102 did not induce early CD40-induced signaling events, and it inhibited early kinase and transcription factor activation by CD154 or agonist anti-CD40 mAbs. However, PG102 stimulated normal CD40-mediated TNFR-associated factor (TRAF)2 and TRAF3 degradation. PG102 induced the formation of a CD40 signaling complex that contained decreased amounts of both TRAF2 and TRAF3 and TRAF2-associated signaling proteins. Additionally, PG102-induced CD40 signaling complexes failed to recruit TRAF6 to detergent-insoluble membrane fractions. Fab fragments of PG102, while retaining CD40 binding, did not induce TRAF degradation, nor could they inhibit CD154-stimulated B cell signaling, indicating that CD40 aggregation is required for the signaling inhibition induced by PG102. The antagonistic impact of PG102 on CD40 signaling reveals that the manner of CD40 ligation can determine sharply different outcomes for CD40 signaling and suggests that such information can be used to therapeutically manipulate these outcomes.

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Bankert

Oxley

Smith

et al. 2015

The Journal of Immunology

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“…Also, the establishment of chimerism in CD154-deficient recipients was shown to require blockade of the CD80/CD86-CD28 pathway (32). Likewise, blockade of both interactions was necessary to prevent acute rejection of solid allografts (18). The rationale for combining CTLA-4Ig and MR1 has previously been reviewed (3,4).…”

Section: Discussionmentioning

confidence: 99%

“…Experimental blocking of the CD40-CD154 or the CD80/ CD86-CD28 costimulatory interactions has been shown to prolong allograft survival in rodent models (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). However, in nonhuman primate studies, blockade of a single pathway is not enough to induce tolerance and only prevents the acute rejection of solid allografts as long as the blockade is maintained (18). Likewise, in human MLR, blockade of both costimulatory interactions is essential for the induction of nonresponsiveness (19).…”

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confidence: 99%

Contribution of Regulatory T Cells and Effector T Cell Deletion in Tolerance Induction by Costimulation Blockadel

Verbinnen

Billiau²,

Vermeiren

et al. 2008

The Journal of Immunology

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Blocking of costimulatory signals for T cell activation leads to tolerance in several transplantation models, but the underlying mechanisms are incompletely understood. We analyzed the involvement of regulatory T cells (Treg) and deletion of alloreactive cells in the induction and maintenance of tolerance after costimulation blockade in a mouse model of graft-vs-host reaction. Injection of splenocytes from the C57BL/6 parent strain into a sublethally irradiated F1 offspring (C57BL/6 × C3H) induced a GVHR characterized by severe pancytopenia. Treatment with anti-CD40L mAb and CTLA4-Ig every 3 days during 3 wk after splenocyte injection prevented disease development and induced a long-lasting state of stable mixed chimerism (>120 days). In parallel, host-specific tolerance was achieved as demonstrated by lack of host-directed alloreactivity of donor-type T cells in vitro and in vivo. Chimerism and tolerance were also obtained after CD25+ cell-depleted splenocyte transfer, showing that CD25+ natural Treg are not essential for tolerance induction. We further show that costimulation blockade results in enhanced Treg cell activity at early time points (days 6–30) after splenocyte transfer. This was demonstrated by the presence of a high percentage of Foxp3+ cells among donor CD4+ cells in the spleen of treated animals, and our finding that isolated donor-type T cells at an early time point (day 30) after splenocyte transfer displayed suppressive capacity in vitro. At later time points (>30 days after splenocyte transfer), clonal deletion of host-reactive T cells was found to be a major mechanism responsible for tolerance.

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“…However, the efficacy of this MAb in combination with anti-human CD40 has been shown recently in a rhesus monkey kidney transplantation study. 27 The present study demonstrates the functional in vivo activity of ch5D12 and chFun-1 MAbs in a rhesus monkey model of systemic transduction with an Ad vector, for preventing the immune response against the gene therapy vehicle. These results are encouraging as they confirm that it is feasible to block the humoral response induced by systemic injection of an Ad vector, allowing readministration of the vector.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of costimulation allows for repeated systemic administration of adenoviral vector in rhesus monkeys

et al. 2004

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Immunogenicity of recombinant adenoviral (Ad) vectors severely hampers the clinical development of gene therapy protocols using repeated vector administrations. Inhibition of costimulation by APCs was explored as a strategy to circumvent the immune response against Ad particles. This strategy was tested in rhesus monkeys, treated transiently with chimeric anti-human CD40 and anti-human CD86 antagonist monoclonal antibodies (MAbs) at the time of systemic administration of a recombinant Ad vector. After Ad vector administration in the absence of immunosuppressive treatment, transgene expression in the serum lasted about 3-4 weeks. All control animals developed a strong neutralizing antibody (NAb) response to the Ad particles, which totally prevented efficient administration of a second vector, as shown by the lack of transgene expression. Treatment with anti-CD40 and anti-CD86 chimeric MAbs delayed or blocked the development of a humoral response against Ad and the infiltration of CD8 þ lymphocytes into the liver. This resulted in (i) increased persistence of Ad-transduced cells after injection of a first vector encoding a nonimmunogenic transgene, and (ii) the possibility of readministering a second Ad vector with significant efficacy. In both respects, the combined blockade of CD40 and CD86 was more efficient than treatment with anti-CD40 alone. This study shows for the first time in non-human primates that blocking CD40 and CD86 costimulatory molecules represents a promising strategy to inhibit immune responses against an Ad vector injected systemically.

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Prevention of kidney allograft rejection using anti-CD40 and anti-CD86 in primates

Cited by 120 publications

References 29 publications

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Contribution of Regulatory T Cells and Effector T Cell Deletion in Tolerance Induction by Costimulation Blockadel

Inhibition of costimulation allows for repeated systemic administration of adenoviral vector in rhesus monkeys

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