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Impact of sex, MHC, and age of recipients on the therapeutic effect of transferred leukocytes from cancer-resistant SR/CR mice.

Stehle JR, Blanks MJ, Riedlinger G, Kim-Shapiro JW, Sanders AM, Adams JM, Willingham MC, Cui Z - BMC Cancer (2009)

Bottom Line: In contrast, male donor leukocytes were greatly affected in the female recipients.The irradiation of donor leukocytes prior to transfers had a profound suppressive effect on donor leukocyte functions, possibly as a result of impaired transcription.The cryopreserving of donor leukocytes in liquid nitrogen had no apparent effect on donor leukocyte functions, except for a small loss of cell number after revival from freezing.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Wake Forest University School of Medicine Winston-Salem, North Carolina 27157, USA. jstehle@wfubmc.edu

ABSTRACT

Background: Spontaneous Regression/Complete Resistant (SR/CR) mice are resistant to cancer through a mechanism that is mediated entirely by leukocytes of innate immunity. Transfer of leukocytes from SR/CR mice can confer cancer resistance in wild-type (WT) recipients in both preventative and therapeutic settings. In the current studies, we investigated factors that may impact the efficacy and functionality of SR/CR donor leukocytes in recipients.

Results: In sex-mismatched transfers, functionality of female donor leukocytes was not affected in male recipients. In contrast, male donor leukocytes were greatly affected in the female recipients. In MHC-mismatches, recipients of different MHC backgrounds, or mice of different strains, showed a greater negative impact on donor leukocytes than sex-mismatches. The negative effects of sex-mismatch and MHC-mismatch on donor leukocytes were additive. Old donor leukocytes performed worse than young donor leukocytes in all settings including in young recipients. Young recipients were not able to revive the declining function of old donor leukocytes. However, the function of young donor leukocytes declined gradually in old recipients, suggesting that an aged environment may contain factors that are deleterious to cellular functions. The irradiation of donor leukocytes prior to transfers had a profound suppressive effect on donor leukocyte functions, possibly as a result of impaired transcription. The cryopreserving of donor leukocytes in liquid nitrogen had no apparent effect on donor leukocyte functions, except for a small loss of cell number after revival from freezing.

Conclusion: Despite the functional suppression of donor leukocytes in sex- and MHC-mismatched recipients, as well as old recipients, there was a therapeutic time period during the initial few weeks during which donor leukocytes were functional before their eventual rejection or functional decline. The eventual rejection of donor leukocytes will likely prevent donor leukocyte engraftment which would help minimize the risk of transfusion-associated graft-versus-host disease. Therefore, using leukocytes from healthy donors with high anti-cancer activity may be a feasible therapeutic concept for treating malignant diseases.

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Related in: MedlinePlus

Functionality of donor leukocytes in mismatched recipients. The pooled donor leukocytes were evenly given to the recipients intraperitoneally (IP). After transfers of donor leukocytes, recipient mice were challenged with 1 × 106 S180 cells IP. The percent survival of the recipient mice was presented to indicate the functionality of the transferred donor leukocytes after the first challenge (left bars, 1 day after the transfer), second challenge (middle bars, 6 weeks after the transfer) and third challenge (right bars, 12 weeks after the transfer). All recipient mice were WT mice that were sensitive to S180 challenges. For the matched controls, 6 male BALB/c recipients were given male BALB/c SR/CR donor leukocytes and 6 female BALB/c recipients were given female BALB/c SR/CR donor leukocytes. For the sex mismatch, 6 female BALB/c recipients were given male BALB/c SR/CR donor leukocytes; 6 male BALB/c recipients were given female BALB/c SR/CR donor leukocytes. For the MHC mismatch, 6 male C57BL/6 mice were given male BALB/c SR/CR leukocytes and 6 female C57BL/6 mice were given female BALB/c SR/CR leukocytes. For the sex and MHC double mismatch, 6 female C57BL/6 mice were given male BALB/c SR/CR leukocytes and 6 male C57BL/6 mice were given female BALB/c SR/CR leukocytes. The percent survival for each of the adoptive transfers remains unchanged after each subsequent S180 challenge. The overall survival for each experimental group was as follows: matched is 100%, sex mismatch is 83%, MHC mismatch is 58%, and MHC + sex mismatch is 42%.
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Figure 1: Functionality of donor leukocytes in mismatched recipients. The pooled donor leukocytes were evenly given to the recipients intraperitoneally (IP). After transfers of donor leukocytes, recipient mice were challenged with 1 × 106 S180 cells IP. The percent survival of the recipient mice was presented to indicate the functionality of the transferred donor leukocytes after the first challenge (left bars, 1 day after the transfer), second challenge (middle bars, 6 weeks after the transfer) and third challenge (right bars, 12 weeks after the transfer). All recipient mice were WT mice that were sensitive to S180 challenges. For the matched controls, 6 male BALB/c recipients were given male BALB/c SR/CR donor leukocytes and 6 female BALB/c recipients were given female BALB/c SR/CR donor leukocytes. For the sex mismatch, 6 female BALB/c recipients were given male BALB/c SR/CR donor leukocytes; 6 male BALB/c recipients were given female BALB/c SR/CR donor leukocytes. For the MHC mismatch, 6 male C57BL/6 mice were given male BALB/c SR/CR leukocytes and 6 female C57BL/6 mice were given female BALB/c SR/CR leukocytes. For the sex and MHC double mismatch, 6 female C57BL/6 mice were given male BALB/c SR/CR leukocytes and 6 male C57BL/6 mice were given female BALB/c SR/CR leukocytes. The percent survival for each of the adoptive transfers remains unchanged after each subsequent S180 challenge. The overall survival for each experimental group was as follows: matched is 100%, sex mismatch is 83%, MHC mismatch is 58%, and MHC + sex mismatch is 42%.

Mentions: To determine the impact of different recipient MHC and sex backgrounds on transferred anti-cancer activity, we performed a set of experiments where the mice were intentionally mismatched for strain and sex. For the sex-mismatch, SR/CR BALB/c male donor leukocytes were transferred into WT BALB/c female recipients, or SR/CR BALB/c female donor leukocytes were transferred into WT BALB/c males. For the MHC-mismatch, SR/CR BALB/c female donor leukocytes were transferred into WT C57BL/6 female recipients, or SR/CR BALB/c male donor leukocytes were transferred into WT C57BL/6 male recipients. For the sex- and MHC- double mismatch, SR/CR BALB/c male donor leukocytes were transferred into female WT C57BL/6 recipients, or SR/CR BALB/c female donor leukocytes were transferred into WT C57BL/6 males. All WT recipient mice were then challenged with 1 × 106 S180 cells, 24 hours after the adoptive transfer, to evaluate the anticancer activity of the transferred leukocytes. The surviving mice were then challenged with 1 × 106 S180 two more times with 5-6 week intervals between the injections. As expected, the sex- and MHC-matched controls showed 100% overall survival after all three S180 challenges (Figure 1). The sex-mismatch mice resulted in an overall survival of 83% (Figure 1) after three S180 challenges. The MHC-mismatch resulted in a reduction of overall survival (58%) which was maintained for each of the subsequent tumor challenges (Figure 1). When the recipients were mismatched for both MHC and sex, the overall survival dropped to approximately 42%, but remained unchanged after the first tumor challenge. Interestingly, when the recipients were evaluated by sex (Figure 2), the female recipients displayed a lower survival in all mismatched groups tested. When the transfers were mismatched for sex, 100% survival was observed in the male recipients with only 67% survival in the female recipients (Figure 2). When the recipients were MHC-mismatched, the male recipients had 83% survival while the females only had 33% survival (Figure 2). Finally, in the double-mismatch for sex and MHC, male recipients had a higher survival percentage (67%) when compared to the female recipients (17%) (Figure 2). All of the failed adoptive transfers were observed during the first challenge with S180 since the percent survival remained unchanged throughout the second and third challenges for all groups evaluated (Figure 1).


Impact of sex, MHC, and age of recipients on the therapeutic effect of transferred leukocytes from cancer-resistant SR/CR mice.

Stehle JR, Blanks MJ, Riedlinger G, Kim-Shapiro JW, Sanders AM, Adams JM, Willingham MC, Cui Z - BMC Cancer (2009)

Functionality of donor leukocytes in mismatched recipients. The pooled donor leukocytes were evenly given to the recipients intraperitoneally (IP). After transfers of donor leukocytes, recipient mice were challenged with 1 × 106 S180 cells IP. The percent survival of the recipient mice was presented to indicate the functionality of the transferred donor leukocytes after the first challenge (left bars, 1 day after the transfer), second challenge (middle bars, 6 weeks after the transfer) and third challenge (right bars, 12 weeks after the transfer). All recipient mice were WT mice that were sensitive to S180 challenges. For the matched controls, 6 male BALB/c recipients were given male BALB/c SR/CR donor leukocytes and 6 female BALB/c recipients were given female BALB/c SR/CR donor leukocytes. For the sex mismatch, 6 female BALB/c recipients were given male BALB/c SR/CR donor leukocytes; 6 male BALB/c recipients were given female BALB/c SR/CR donor leukocytes. For the MHC mismatch, 6 male C57BL/6 mice were given male BALB/c SR/CR leukocytes and 6 female C57BL/6 mice were given female BALB/c SR/CR leukocytes. For the sex and MHC double mismatch, 6 female C57BL/6 mice were given male BALB/c SR/CR leukocytes and 6 male C57BL/6 mice were given female BALB/c SR/CR leukocytes. The percent survival for each of the adoptive transfers remains unchanged after each subsequent S180 challenge. The overall survival for each experimental group was as follows: matched is 100%, sex mismatch is 83%, MHC mismatch is 58%, and MHC + sex mismatch is 42%.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2749872&req=5

Figure 1: Functionality of donor leukocytes in mismatched recipients. The pooled donor leukocytes were evenly given to the recipients intraperitoneally (IP). After transfers of donor leukocytes, recipient mice were challenged with 1 × 106 S180 cells IP. The percent survival of the recipient mice was presented to indicate the functionality of the transferred donor leukocytes after the first challenge (left bars, 1 day after the transfer), second challenge (middle bars, 6 weeks after the transfer) and third challenge (right bars, 12 weeks after the transfer). All recipient mice were WT mice that were sensitive to S180 challenges. For the matched controls, 6 male BALB/c recipients were given male BALB/c SR/CR donor leukocytes and 6 female BALB/c recipients were given female BALB/c SR/CR donor leukocytes. For the sex mismatch, 6 female BALB/c recipients were given male BALB/c SR/CR donor leukocytes; 6 male BALB/c recipients were given female BALB/c SR/CR donor leukocytes. For the MHC mismatch, 6 male C57BL/6 mice were given male BALB/c SR/CR leukocytes and 6 female C57BL/6 mice were given female BALB/c SR/CR leukocytes. For the sex and MHC double mismatch, 6 female C57BL/6 mice were given male BALB/c SR/CR leukocytes and 6 male C57BL/6 mice were given female BALB/c SR/CR leukocytes. The percent survival for each of the adoptive transfers remains unchanged after each subsequent S180 challenge. The overall survival for each experimental group was as follows: matched is 100%, sex mismatch is 83%, MHC mismatch is 58%, and MHC + sex mismatch is 42%.
Mentions: To determine the impact of different recipient MHC and sex backgrounds on transferred anti-cancer activity, we performed a set of experiments where the mice were intentionally mismatched for strain and sex. For the sex-mismatch, SR/CR BALB/c male donor leukocytes were transferred into WT BALB/c female recipients, or SR/CR BALB/c female donor leukocytes were transferred into WT BALB/c males. For the MHC-mismatch, SR/CR BALB/c female donor leukocytes were transferred into WT C57BL/6 female recipients, or SR/CR BALB/c male donor leukocytes were transferred into WT C57BL/6 male recipients. For the sex- and MHC- double mismatch, SR/CR BALB/c male donor leukocytes were transferred into female WT C57BL/6 recipients, or SR/CR BALB/c female donor leukocytes were transferred into WT C57BL/6 males. All WT recipient mice were then challenged with 1 × 106 S180 cells, 24 hours after the adoptive transfer, to evaluate the anticancer activity of the transferred leukocytes. The surviving mice were then challenged with 1 × 106 S180 two more times with 5-6 week intervals between the injections. As expected, the sex- and MHC-matched controls showed 100% overall survival after all three S180 challenges (Figure 1). The sex-mismatch mice resulted in an overall survival of 83% (Figure 1) after three S180 challenges. The MHC-mismatch resulted in a reduction of overall survival (58%) which was maintained for each of the subsequent tumor challenges (Figure 1). When the recipients were mismatched for both MHC and sex, the overall survival dropped to approximately 42%, but remained unchanged after the first tumor challenge. Interestingly, when the recipients were evaluated by sex (Figure 2), the female recipients displayed a lower survival in all mismatched groups tested. When the transfers were mismatched for sex, 100% survival was observed in the male recipients with only 67% survival in the female recipients (Figure 2). When the recipients were MHC-mismatched, the male recipients had 83% survival while the females only had 33% survival (Figure 2). Finally, in the double-mismatch for sex and MHC, male recipients had a higher survival percentage (67%) when compared to the female recipients (17%) (Figure 2). All of the failed adoptive transfers were observed during the first challenge with S180 since the percent survival remained unchanged throughout the second and third challenges for all groups evaluated (Figure 1).

Bottom Line: In contrast, male donor leukocytes were greatly affected in the female recipients.The irradiation of donor leukocytes prior to transfers had a profound suppressive effect on donor leukocyte functions, possibly as a result of impaired transcription.The cryopreserving of donor leukocytes in liquid nitrogen had no apparent effect on donor leukocyte functions, except for a small loss of cell number after revival from freezing.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Wake Forest University School of Medicine Winston-Salem, North Carolina 27157, USA. jstehle@wfubmc.edu

ABSTRACT

Background: Spontaneous Regression/Complete Resistant (SR/CR) mice are resistant to cancer through a mechanism that is mediated entirely by leukocytes of innate immunity. Transfer of leukocytes from SR/CR mice can confer cancer resistance in wild-type (WT) recipients in both preventative and therapeutic settings. In the current studies, we investigated factors that may impact the efficacy and functionality of SR/CR donor leukocytes in recipients.

Results: In sex-mismatched transfers, functionality of female donor leukocytes was not affected in male recipients. In contrast, male donor leukocytes were greatly affected in the female recipients. In MHC-mismatches, recipients of different MHC backgrounds, or mice of different strains, showed a greater negative impact on donor leukocytes than sex-mismatches. The negative effects of sex-mismatch and MHC-mismatch on donor leukocytes were additive. Old donor leukocytes performed worse than young donor leukocytes in all settings including in young recipients. Young recipients were not able to revive the declining function of old donor leukocytes. However, the function of young donor leukocytes declined gradually in old recipients, suggesting that an aged environment may contain factors that are deleterious to cellular functions. The irradiation of donor leukocytes prior to transfers had a profound suppressive effect on donor leukocyte functions, possibly as a result of impaired transcription. The cryopreserving of donor leukocytes in liquid nitrogen had no apparent effect on donor leukocyte functions, except for a small loss of cell number after revival from freezing.

Conclusion: Despite the functional suppression of donor leukocytes in sex- and MHC-mismatched recipients, as well as old recipients, there was a therapeutic time period during the initial few weeks during which donor leukocytes were functional before their eventual rejection or functional decline. The eventual rejection of donor leukocytes will likely prevent donor leukocyte engraftment which would help minimize the risk of transfusion-associated graft-versus-host disease. Therefore, using leukocytes from healthy donors with high anti-cancer activity may be a feasible therapeutic concept for treating malignant diseases.

Show MeSH
Related in: MedlinePlus