Experimental myocarditis: Enhancement by the use of pertussis vaccine in Lewis rats

Friedman, I.; Ron, Naomi; Laufer, A.; Davies, A.

doi:10.1007/bf02112726

Cited by 11 publications

(4 citation statements)

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“…In studies 1 and 2, LEW/HanHsd rats were used, whereas in study 3, the LEW/SsNHsd substrain was used, providing the opportunity to test the hypothesis mentioned above. In this substrain, the immune system is more active compared to the HanHsd strain and shows an enhanced (auto)-immune response [ 13 - 17 ]. In these rats, 50% of tumors in the control group went into spontaneous regression after reaching an average tumor volume of ≈ 3 cm 3 , probably due to an immune response against the growing tumor.…”

Section: Discussionmentioning

confidence: 99%

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Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate in combination with RAD001 treatment: further investigations on tumor metastasis and response in the rat pancreatic CA20948 tumor model

et al. 2014

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BackgroundPreviously, we reported on the unexpected development of distant metastases in the subcutaneous rat pancreas CA20948 tumor model after 4.5 weeks of treatment with RAD001-only or in combination with [177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE) (Cancer Res. 73:12-8, 2013). Moreover, the combination therapy was less effective compared to 177Lu-DOTATATE-only. In the current study, we address the following questions: (1) Why was the combination therapy less effective? Is 177Lu-DOTATATE tumor uptake affected by pretreatment with RAD001? (2) Could sudden cessation of RAD001 therapy cause the development of distant metastases? (3) Is 177Lu-DOTATATE an effective treatment option for these metastases?MethodsLewis rats (HanHsd or SsNHsd substrain with a slight difference in immune response) bearing subcutaneous CA20948 tumors were treated with either 125 or 275 MBq 177Lu-DOTATATE, RAD001, or their combination. RAD001 was given twice a week for 4.5 or 12 weeks, whereas 177Lu-DOTATATE was given as a single injection. When combined, RAD001 was started either 3 days prior to or 3 days post administration of 177Lu-DOTATATE. SPECT/CT was performed to quantify 177Lu-DOTATATE tumor uptake. Where indicated, primary tumors were surgically removed when tumor size is >6,000 mm3 to enable monitoring for possible metastasis. If metastases were suspected, an 111In-DTPA-octreotide SPECT/CT scan was performed. Seven rats with metastases were treated with 400 MBq 177Lu-DOTATATE.ResultsLu-DOTATATE tumor uptake was not significantly affected by RAD001 pretreatment. The occurrence of metastases after RAD001 treatment was not dose dependent in the dose range tested, nor was it related to the duration of RAD001 treatment. In the experiment in which the LEW/SsNsd substrain was used, only 12.5% of RAD001-treated rats showed complete response (CR), compared to 50% tumor regression in the control group. Re-treatment with a high dose of 177Lu-DOTATATE resulted in CR in only two out of seven animals.ConclusionLess effective anti-tumor effects after the combination of RAD001 + 177Lu-DOTATATE could not be explained by reduced 177Lu-DOTATATE tumor uptake after RAD001. Our current data support RAD001-induced immune suppression as the reason for this observation. No evidence was found that cessation of RAD001 treatment caused development of metastases. Metastases appeared to be less sensitive to 177Lu-DOTATATE treatment than primary tumors.

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Section: Discussionmentioning

confidence: 99%

“…We used LEW/HanHsd Lewis rats, and where indicated, we also included rats from the LEW/SsNHsd substrain. In the LEW/SsNHsd substrain, the immune system shows an enhanced CD4+ and CD8+ T cell (auto)-immune response [ 13 - 17 ]. This autoimmunity is linked to an increased tumor immunity [ 18 , 19 ].…”

Section: Methodsmentioning

confidence: 99%

Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate in combination with RAD001 treatment: further investigations on tumor metastasis and response in the rat pancreatic CA20948 tumor model

et al. 2014

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“…F riedman et al [4] increased this incidence in rats injected with rat heart, by inclusion of Haemophilus per tussis vaccine in Freund's adjuvant mixture, 8 of 13 animals showing car diac changes. On the other hand, W egelius and Jokinen [5,6] have re cently failed to observe any significant heart lesions in rabbits immunized with rabbit heart homogenates without adjuvants, although appreciable kidney damage was produced.…”

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confidence: 99%

The Cardiac Auto-Immune System

Halbert¹,

Lin²,

Smith³

1973

Int Arch Allergy Immunol

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Rabbits repeatedly immunized for a prolonged period of time with homogenates of rabbit heart in complete Freund’s adjuvant developed a focal myocarditis which appeared to be of auto-immune pathogenesis. The lesions were characterized by focal myocardial cell necrosis, phagocytosis of the cell residues, followed by scarring. Within the scar, shriveled and apparently damaged myocardial cells persisted. The cardiac lesions were not correlated with the intensity of the humoral cardiac auto-immune responses in these animals. Several of the rabbits immunized with rabbit heart showed interstitial tubular kidney lesions, in confirmation of data reported by others. No correlation was found between the extent of the cardiac and kidney lesions in animals showing both. Some of the rabbits with severe cardiac changes had normal kidneys histologically. Of five rabbits immunized with small amounts of partially purified soluble rabbit cardiac antigens, two showed similar but minimal myocardial lesions. Cardiac lesions were not found in untreated controls or in rabbits immunized with a number of different complex antigen mixtures for varying, often prolonged, periods of time. The latter group included four rabbits immunized with human heart homogenates.

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“…In addition, in vitro studies showed that lymphocytes sen sitized to heart extracts are cytotoxic to beating rat heart cultures. Of in terest was the finding that lymphocytes sensitized to group A streptococ ci were also cytotoxic to heart cultures while control lymphocytes sensi tized to streptococcus viridans were not [2,5].…”

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confidence: 99%