In Vivo Characterization of Rabbit Anti-Mouse Thymocyte Globulin: A Surrogate for Rabbit Anti-Human Thymocyte Globulin

Ruzek, Melanie C.; Neff, Kathleen; Luong, Michael; Smith, Karen; Culm-Merdek, Kerry; Richards, Susan; Williams, John M.; Perricone, Michael A.; Garman, Richard D.

doi:10.1097/tp.0b013e3181abc061

Cited by 38 publications

(43 citation statements)

References 43 publications

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“…3B; data not shown). As observed in previously reported studies, mATG has a greater effect on CD8 + T cell depletion than CD4 + T cell depletion (22), and this bias is maintained with methotrexate administration (Fig. 2B).…”

Section: Single-cycle Methotrexate Restores Matg-mediated T Cell Deplsupporting

confidence: 69%

“…Mice were housed and maintained in accordance with the Guide for the Care and Use of Laboratory Animals and under American Association for Accreditation of Laboratory Animal Care accreditation, and all animal procedures were approved by the Institutional Animal Care and Use Committee. A murine version of Thymoglobulin (mATG) was generated by immunizing rabbits with a mixture of mouse thymocytes as described previously (22). mATG was administered as an i.p.…”

Section: Methodsmentioning

confidence: 99%

“…In particular, as T regulatory cells have been associated with longterm graft survival in transplantation (23,24,30,31), are induced by Thymoglobulin and mATG (22,25,26,32,33), and have previously been demonstrated to be responsible for delayed graft rejection following mATG (16), CD3 + Foxp3 + cells, which bear a phenotype consistent with regulatory T cells, were evaluated. To assess histologic changes in long-surviving grafts, cardiac grafts were collected from the mATG and methotrexate combinationtreated group and the untreated syngeneic group at least 100 d after transplantation.…”

Section: Matg and Methotrexate Cotreatment Reduces Allograft Rejectiomentioning

confidence: 99%

“…mATG is purified IgG from rabbits immunized with mouse thymocytes and behaves similarly in mice to Thymoglobulin in humans (22). mATG depletes CD4 + and CD8 + T cells, expands the percentage of functional T regulatory cells in mice (22), and through these mechanisms is effective at delaying rejection of allogeneic heart and skin transplants in mice (Ref. 23; J. Williams, unpublished observations).…”

mentioning

confidence: 99%

“…We explored whether low-dose methotrexate can reduce anti-ATG Ab responses in nonclinical studies using a murine version of Thymoglobulin, mATG. mATG is purified IgG from rabbits immunized with mouse thymocytes and behaves similarly in mice to Thymoglobulin in humans (22). mATG depletes CD4 + and CD8 + T cells, expands the percentage of functional T regulatory cells in mice (22), and through these mechanisms is effective at delaying rejection of allogeneic heart and skin transplants in mice (Ref.…”

mentioning

confidence: 99%

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Transient Low-Dose Methotrexate Induces Tolerance to Murine Anti-Thymocyte Globulin and Together They Promote Long-Term Allograft Survival

Joseph¹,

Neff²,

Richard³

et al. 2012

The Journal of Immunology

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Rabbit anti-thymocyte globulin (Thymoglobulin) effectively treats transplant rejection but induces anti-rabbit Ab responses, which limits routine readministration. Aiming to tolerize anti-rabbit responses, we coadministered a brief methotrexate regimen with a murine version of Thymoglobulin (mATG) for effects on anti-mATG Abs and cardiac allotransplantation in mice. Although both single and three courses of methotrexate could significantly inhibit anti-drug Ab titers to repeated mATG treatment, surprisingly, the single course given at the first mATG administration was most effective (>99% reduction). The transient methotrexate treatment also significantly improved pharmacokinetics and pharmacodynamics of repeated mATG administration. In the cardiac allograft model, the combination of transient mATG and methotrexate given only at the time of transplant dramatically improved allograft survival (>100 d) over either agent alone (<30 d). Anti-drug Ab titers were reduced and mATG exposure was increased which resulted in prolonged rather than enhanced mATG-mediated effects when combined with methotrexate. Moreover, methotrexate administration significantly reduced alloantibodies, suggesting that methotrexate not only decreases anti-drug Ab responses but also reduces Ab responses to multiple tissue-derived alloantigens simultaneously. These data suggest that mATG and methotrexate together can provide long-term allograft survival potentially through the induction of immune tolerance.

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Section: Single-cycle Methotrexate Restores Matg-mediated T Cell Deplsupporting

confidence: 69%

Section: Methodsmentioning

confidence: 99%