Short-course methotrexate and long-term acceptance of fully allogeneic rat cardiac grafts: a possible mechanism of tolerance

Sakuma, Yoshiki; Xiu, Dian Rong; Uchida, Hiroo; Hakamata, Yoji; Takahashi, Masafumi; Murakami, Takashi; Nagai, Hideo; Kobayashi, Eiji

doi:10.1016/s0966-3274(02)00015-1

Cited by 4 publications

(2 citation statements)

References 18 publications

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“…Although early studies had suggested that methotrexate can be beneficial in preclinical and clinical transplantation settings (57,58), methotrexate in transplantation was largely discontinued with the advent of newer drugs. In addition, methotrexate-associated toxicities arising from continued treatment and high-dose regimens have also hindered use.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…2 The immune-unresponsive state induced by methotrexate was found to be related to a number of humoral factors. 3 It remains unclear, however, which of these factors could be used as a biomarker (or biomarkers) to diagnose rejection.…”

Section: Introductionmentioning

confidence: 99%

Proteomic profiling of heterotopic heart-transplanted rats using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry: Potential biomarkers and drug targets

2013

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Objective: Methotrexate and rapamycin demonstrate an additive effect in prolonging cardiac allograft survival in a major histocompatibility complex mismatched rat model. The present study aimed to identify functional proteins involved in the allograft-protective effects of these two agents and reveal potential diagnostic markers for treating rejection. Methods: Serum samples from heterotopic heart-transplanted LEW(RT-1 1 ) rats (either without immunosuppressive treatment or treated with methotrexate alone, rapamycin alone, or methotrexate and rapamycin combined) were analysed by surface-enhanced laser desorption/ ionization time-of-flight mass spectrometry. Protein profiles obtained using a weak cation exchange ProteinChip Õ CM-10 array were then analysed using ProteinChip Õ Software. Results: Of 28 rejection-related proteins identified, isoelectric point and mass information from two potential candidate proteins matched information from the UniProtKB/Swiss-prot database, suggesting them to be complement component C3f fragment and complement component 4A (C4A, anaphylatoxin). Conclusions: Proteomic analysis revealed 28 proteins as potential diagnostic markers of tissue rejection. Of these, 11 proteins may represent targets relating to the additive effects of methotrexate and rapamycin. Two protein peaks, with mass-to-charge ratios of 1950 Da and 8577 Da, may have potential for use in post-transplant diagnosis of rejection.

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Rat Immunology

Mexas¹,

Patil²

2020

The Laboratory Rat

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Short-course methotrexate and long-term acceptance of fully allogeneic rat cardiac grafts: a possible mechanism of tolerance

Cited by 4 publications

References 18 publications

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

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

Proteomic profiling of heterotopic heart-transplanted rats using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry: Potential biomarkers and drug targets

Rat Immunology

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