Studies on Cyclophosphamide-Induced Tolerance to Sheep Erythrocytes

Aisenberg, Alan C.

doi:10.1084/jem.125.5.833

Cited by 112 publications

(50 citation statements)

References 19 publications

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“…Suppression of B and T-cell responses is most pronounced when cyclophosphamide is administered at the same time or within 3 days following antigen challenge but is also seen when the drug is administered 1 or 2 days before exposure to antigen, particularly when higher doses (>100 mg/kg in a mouse) of cyclophosphamide are used. 36 The results of our squirrel monkey toxicology study in which monkeys were pretreated with 31 mg/kg of cyclophosphamide, administered 2 days before intravenous MV-NIS have provided strong support for the proposed dose and dose schedule. The data from this study show that the cyclophosphamide did not cause significant toxicity to the animals but weakly suppressed the antiviral immune response sufficient to facilitate more extensive spread of the virus before its elimination.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacology and Toxicology of Intravenous MV-NIS, an Oncolytic Measles Virus Administered With or Without Cyclophosphamide

et al. 2007

Clin Pharmacol Ther

113

125

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MV-NIS is an oncolytic measles virus encoding the human thyroidal sodium iodide symporter (NIS).Here, we report the results of preclinical pharmacology and toxicology studies conducted in support of our clinical protocol "Phase I Trial of Systemic Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express NIS, with or without Cyclophosphamide, in Patients with Recurrent or Refractory Multiple Myeloma." Dose-response studies in the KAS-6/1 myeloma xenograft model demonstrated a minimum effective dose of 4 × 10 6 TCID 50 (tissue culture infectious dose 50)/kg. Toxicity studies in measles-naive squirrel monkeys and measles-susceptible transgenic mice were negative at intravenous doses up to 10 8 and 4 × 10 8 TCID 50 /kg, respectively. Abundant viral mRNA, maximal on day 8, was detected in cheek swabs of squirrel monkeys, more so after pretreatment with cyclophosphamide. On the basis of these data, the safe starting dose of MV-NIS for our clinical protocol was set at 1 -2 × 10 4 TCID 50 /kg (10 6 TCID 50 per patient).Measles virus (MV, family Paramyxoviridae) was isolated in 1954 from the throat washings of a measles patient, David Edmonston. 1 Tissue culture passage resulted in loss of pathogenicity and attenuation of wild-type MV (Figure 1), giving rise to the Edmonston measles vaccines used worldwide today. 2 We recently discovered that attenuated Edmonston strain MV has potent antitumor activity in vitro and in vivo. 3 Intravenous, intratumoral, or intraperitoneal administration of the virus inhibited tumor growth or induced tumor regression in a variety of human tumor xenograft models. [4][5][6][7] To tailor the virus for cancer therapy, we Correspondence: SJ Russell (sjr@mayo.edu). CONFLICT OF INTERESTThe authors declared no conflict of interest. NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2009 October 28. Published in final edited form as:Clin Pharmacol Ther. 2007 December ; 82(6): 700-710. doi:10.1038/sj.clpt.6100409. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscripthave genetically engineered the viral coat protein to display tumor-targeting ligands to enable tumor-specific killing or inserted trackable transgenes into the viral genome to enable noninvasive monitoring of viral gene expression. [8][9][10][11][12] MV-NIS is an Edmonston-lineage MV that expresses the human sodium iodide symporter (hNIS) (Figure 2). 12 The NIS protein is normally expressed in the thyroid, mammary glands, stomach, and salivary tissue. Expression of NIS allows cells to actively transport iodide ions into the cell. Thus, patients with thyroid cancer are typically treated with 131 I to destroy the NIS-expressing thyroid cancer while leaving most normal tissues undamaged. 13 Loss of thyroid function due to the radiotherapy can be treated by replacement therapy with synthetic thyroid hormones. Insertion of NIS into MV facilitates pharmacokinetic evaluation and enhancement of MV oncolytic activity. MV-NIS-infected cells express...

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Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacology and Toxicology of Intravenous MV-NIS, an Oncolytic Measles Virus Administered With or Without Cyclophosphamide

et al. 2007

Clin Pharmacol Ther

113

125

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“…A similar suppression of splenic lymphopoiesis also has been observed in vivo. In a murine model, splenic DNA synthesis was markedly inhibited for 5 days after cyclophosphamide administration (16).…”

Section: Discussionmentioning

confidence: 99%

“…This prolonged inhibition of proliferative responses may be an important factor in the sustained immunosuppressive activity of cyclophospamide (9,16 It is noteworthy that PPD-sensitive cells surviving administration of cyclophosphamide can elaborate this lymphokine but are markedly suppressed in their capacity to proliferate. The reasons for these discordant values are not completely known.…”

Section: Discussionmentioning

confidence: 99%

Effects of cytotoxic immunosuppressants on tuberculin-sensitive lymphocytes in guinea pigs.

Winkelstein¹

1975

J. Clin. Invest.

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“…D rug-induced tolerance that consists of a combination of an Ag and an antimitotic drug was intensively studied in many laboratories in the 1960s and 1970s (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Clinically applicable methods to achieve a long-lasting tolerance of solid organs (especially of the skin), however, have not been established by a short course of the Ag plus immunosuppressive drug treatment (2, 3-8, 10, 11).…”

Section: Induction Of Permanent Mixed Chimerism and Skin Allograft Tomentioning

confidence: 99%

Induction of Permanent Mixed Chimerism and Skin Allograft Tolerance Across Fully MHC-Mismatched Barriers by the Additional Myelosuppressive Treatments in Mice Primed with Allogeneic Spleen Cells Followed by Cyclophosphamide

Tomita¹,

Yoshikawa

Zhang³

et al. 2000

The Journal of Immunology

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A pure method of drug (cyclophosphamide plus busulfan)-induced skin allograft tolerance in mice that can regularly overcome fully H-2-mismatched barriers in mice has been established. The components of the method are i.v. administration of 1 × 108 allogeneic spleen cells on day 0, i.p. injection of 200 mg/kg CP and 25 mg/kg busulfan on day 2, and i.v. injection of T cell-depleted 1 × 107 bone marrow cells from the same donor on day 3. Recipient B10 (H-2b; IE−) mice prepared with this conditioning developed donor-specific tolerance, and long-lasting survival of skin allografts was shown in almost of the recipient mice. In the tolerant B10 mice prepared with new conditioning, stable multilineage mixed chimerism was observed permanently, and IE-reactive Vβ11+ T cells were reduced in periphery as seen in untreated B10.D2 (H-2d; IE+) mice. The specific tolerant state was confirmed by the specific abrogation against donor Ag in the assays of CTL activity and MLR and donor-specific acceptance in the second skin grafting. These results demonstrated that the limitation of standard protocol of cyclophosphamide-induced tolerance, which have been reported by us since 1984, can be overcome by the additional treatments with the myelosuppressive drug busulfan, followed by 1 × 107 T cell-depleted bone marrow cells. To our knowledge, this is the first report to induce allograft tolerance with a short course of the Ag plus immunosuppressive drug treatment without any kind of mAbs (pure drug-induced tolerance).

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Studies on Cyclophosphamide-Induced Tolerance to Sheep Erythrocytes

Cited by 112 publications

References 19 publications

Preclinical Pharmacology and Toxicology of Intravenous MV-NIS, an Oncolytic Measles Virus Administered With or Without Cyclophosphamide

Preclinical Pharmacology and Toxicology of Intravenous MV-NIS, an Oncolytic Measles Virus Administered With or Without Cyclophosphamide

Effects of cytotoxic immunosuppressants on tuberculin-sensitive lymphocytes in guinea pigs.

Induction of Permanent Mixed Chimerism and Skin Allograft Tolerance Across Fully MHC-Mismatched Barriers by the Additional Myelosuppressive Treatments in Mice Primed with Allogeneic Spleen Cells Followed by Cyclophosphamide

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