Судороги и кома как осложнения, связанные с токсичностью

Íîâîñòè êëåòî÷íûõ òåõíîëîãèé
ôóíêöèîíèðóùåé èììóííîé ñèñòåìå, òåì áîëåå, ÷òî âñå âûñîêîàíòèãåííûå êëåòêè áûëè óäàëåíû èç òðàíñïëàíòàòà.
Êîðåéñêèå èññëåäîâàòåëè íà÷àëè êëèíè÷åñêóþ ïðîãðàììó ïî òðàíñïëàíòàöèè ñòâîëîâûõ êëåòîê ÏÊ äëÿ ëå÷åíèÿ ÒÑÌ
ËÈÒÅÐÀÒÓÐÀ:
1. Áåðñåí¸â À.Â. Ïåðñïåêòèâû èñïîëüçîâàíèÿ êëåòîê ïóïîâèííîé êðîâè
äëÿ òåðàïèè íåãåìàòîëîãè÷åñêèõ çàáîëåâàíèé. Êëåòî÷íàÿ òðàíñïëàíòîëîãèÿ
è òêàíåâàÿ èíæåíåðèÿ.
http://celltranspl.ru/journal/publications/?MESSAGES[1]=
SHOW_PUBLICATION&PUBLICATION_ID=812
2. Paralyzed woman walks again after stem cell therapy. World - AFP,
November 28, 2004.
http://www.cordblood.com/cord_blood_news/stem_cell_news/
a_paralyzed.asp
3. Jeong J.A., Gang E.J., Hong S.H. et al . Rapid neural differentiation of human
cord blood-derived mesenchymal stem cells. Neuroreport. 2004; 15: 1731-4.
4. Kuh S.U., Cho Y.E., Yoon D.H. et al. Functional recovery after human umbilical
cord blood cells transplantation with brain-derived neutrophic factor into the
spinal cord injured rat. Acta Neurochir. (Wien) 2005; 147: 985-92.
5. Zhao Z.M., Li H.J., Liu H.Y. et al. Intraspinal transplantation of CD34+ human
umbilical cord blood cells after spinal cord hemisection injury improves functional
31
â Seoul National University 2 ãîäà íàçàä. Â íàñòîÿùåå âðåìÿ
ïðîäîëæàåòñÿ I ôàçà èñïûòàíèé, êîòîðàÿ ïðèçâàíà ïîäòâåðäèòü áåçîïàñíîñòü ìåòîäà è ïîçâîëèò îòâåòèòü íà íåêîòîðûå äèñêóññèîííûå âîïðîñû.
recovery in adult rats. Cell Transplant. 2004; 13: 113-22.
6. Mareschi K., Biasin E., Piacibell W. et al . Isolation of human mesenchymal
stem cells: bone marrow versus umbilical cord blood. Haematologica 2001;
86:1099-100.
7. Wexler S.A., Donaldson C., Denning-Kendall P. et al . Adult bone marrow is
a rich source of human mesenchymal ‘stem’ cells but umbilical cord and mobilized
adult blood are not. Br. J. Haematol. 2003; 121: 368-74.
8. Lee O.K., Kuo T.K., Chen W.M. et al . Isolation of multi-potent mesenchymal
stem cells from umbilical cord blood. Blood 2004; 103: 1669-75.
9. Knoller N., Auerbach G., Fulga V. et al. Clinical experience using incubated
autologous macrophages as a treatment for complete spinal cord injury: phase I
study results. J. Neurosurg. Spine 2005; 3: 173-11.
10. Hashimoto M., Nitta A., Fukumitsu H. et al. Inflammation-induced
GDNF improves locomotor function after spinal cord injury. Neuroreport.
2005; 16: 99-102.
11. Schwartz M., Yoles E. Macrophages and dendritic cells treatment of spinal
cord injury: from the bench to the clinic. Acta Neurochir. Suppl. 2005; 93: 147-50.
Ïîäãîòîâèë À.Â. Áåðñåíåâ
Ïî ìàòåðèàëàì Cytotherapy 2005; 7: 368-73
Ñóäîðîãè è êîìà êàê îñëîæíåíèÿ, ñâÿçàííûå
ñ òîêñè÷íîñòüþ êðèîïðîòåêòîðà (ÄÌÑÎ) ïðè èíôóçèè
ãåìîïîýòè÷åñêèõ êëåòîê â êëèíèêå òðàíñïëàíòàöèè
êîñòíîãî ìîçãà
Äèìåòèëñóëüôîêñèä (ÄÌÑÎ) äî ñèõ ïîð îñòà¸òñÿ îáùåïðèíÿòûì è ñàìûì ðàñïðîñòðàí¸ííûì êðèîïðîòåêòîðîì âî
âñ¸ì ìèðå, â òîì ÷èñëå è äëÿ êðèîêîíñåðâèðîâàíèÿ ãåìîïîýòè÷åñêèõ êëåòîê â êëèíèêå òðàíñïëàíòàöèè êîñòíîãî ìîçãà
(ÒÊÌ).  ñâÿçè ñ âûñîêîé òîêñè÷íîñòüþ ýòîãî âåùåñòâà â
êëèíèêå ÒÊÌ áûë îïèñàí ðÿä îñëîæíåíèé, â òîì ÷èñëå è
òàêèå òÿæ¸ëûå, êàê ýíöåôàëîïàòèÿ [1,2] è äûõàòåëüíàÿ íåäîñòàòî÷íîñòü [3].
 æóðíàëå Leukemia & Lymphoma, áåëüãèéñêèìè àâòîðàìè îïèñàíî íîâîå íàáëþäåíèå âîçíèêíîâåíèÿ ñóäîðîã è
êîìû, ñâÿçàííûõ ñ òîêñè÷íîñòüþ ÄÌÑÎ ïîñëå àóòîòðàíñïëàíòàöèè ãåìîïîýòè÷åñêèõ êëåòîê.
Ïàöèåíòó 49 ëåò âûïîëíÿëè òðàíñïëàíòàöèþ ìîáèëèçèðîâàííûõ ãåìîïîýòè÷åñêèõ àóòîêëåòîê ïî ïîâîäó ðåöèäèâà
ëèìôîìû. Ïðè èíôóçèè «íåîòìûòûõ» êëåòîê, ñîäåðæàùèõ
10% ÄÌÑÎ, íàáëþäàëè âîçíèêíîâåíèå òîíèêî-êëîíè÷åñêèõ ñóäîðîã. Ïàöèåíòà ïåðåâåëè â ïàëàòó èíòåíñèâíîé òåðàïèè, ãäå ñóäîðîãè áûëè êóïèðîâàíû. Èíôóçèþ îñòàâøåãîñÿ òðàíñïëàíòàòà ïðîâîäèëè ïîñëå 2-êðàòíîé îòìûâêè
êëåòîê, îñëîæíåíèé íå íàáëþäàëè. ×åðåç 17 äíåé, â ñâÿçè ñ
îòñóòñòâèåì ýíãðàôòèíãà áûëî ðåøåíî âûïîëíèòü ïîâòîðíóþ òðàíñïëàíòàöèþ àóòîêëåòîê, êðèîêîíñåðâèðîâàííûõ 4
ãîäà íàçàä. Ïðè âûïîëíåíèè ïîâòîðíîé òðàíñïëàíòàöèè
êëåòêè áûëè äâàæäû îòìûòû îò êðèîïðîòåêòîðà, îäíàêî ó
ïàöèåíòà âíîâü ðàçâèëèñü ãåíåðàëèçîâàííûå ñóäîðîãè è
êîìà. Ïàöèåíò íàõîäèëñÿ â êîìå ïî øêàëå Ãëàçãî (GSC) < 7
íà èñêóññòâåííîé âåíòèëÿöèè ë¸ãêèõ. Èíñòðóìåíòàëüíûå
ìåòîäû (ýëåêòðîýíöåôàëîãðàôèÿ, êîìïüþòåðíàÿ è ìàãíèòíî-ðåçîíàíñíàÿ òîìîãðàôèÿ) ïîäòâåðäèëè íàëè÷èå òÿæ¸ëîé
ýíöåôàëîïàòèè. ×åðåç 35 äíåé ïàöèåíò áûë ïåðåâåä¸í èç
ðåàíèìàöèè â îáùóþ ïàëàòó. Ãåìàòîëîãè÷åñêèå äàííûå ïîêàçàëè íåïîëíóþ ðåêîíñòèòóöèþ êîñòíîãî ìîçãà ñ âîññòàíîâëåíèåì íîðìàëüíîãî êîëè÷åñòâà íåéòðîôèëîâ. ×åðåç
3 ìåñÿöà ïîñëå òðàíñïëàíòàöèè ïàöèåíò óìåð â ñâÿçè ñ îñëîæíåíèÿìè îñíîâíîãî çàáîëåâàíèÿ.
Àâòîðû âïåðâûå îïèñàëè êàðòèíó òîêñè÷åñêîé êîìû, ñâÿçàííîé ñ òîêñè÷íîñòüþ ÄÌÑÎ, îòëè÷íóþ îò ýíöåôàëîïàòèè,
âîçíèêàþøåé ïðè òåðàïèè äðóãèìè âåùåñòâàìè è ïðåïàðàòàìè. Èíòåðåñíî, ÷òî àâòîðû íàáëþäàëè ðàçâèòèå ãåíåðàëèçîâàííûõ ñóäîðîã, âîçíèêàþùèõ íåìåäëåííî âî âðåìÿ èíôóçèè
ðàçìîðîæåííîãî êëåòî÷íîãî òðàíñïëàíòàòà, áåç êàêîãîëèáî îòÿãîù¸ííîãî àíàìíåçà. Äàííûå èíñòðóìåíòàëüíûõ
èññëåäîâàíèé îòðèöàëè íàëè÷èå ýïèëåïòîãåííûõ î÷àãîâ â
ãîëîâíîì ìîçãå. Ðàíåå óæå îïèñûâàëèñü ñóäîðîãè ïîñëå
òðàíñïëàíòàöèè ãåìîïîýòè÷åñêèõ êëåòîê [1, 2], îäíàêî ýòî
íàáëþäåíèå ïîçâîëèëî ÷¸òêî ñâÿçàòü è îïèñàòü ÄÌÑÎâûçâàííóþ ýíöåôàëîïàòèþ.
Òîêñè÷íîñòü êðèîïðîòåêòîðà îñòà¸òñÿ àêòóàëüíîé ïðîáëåìîé ìíîãèõ öåíòðîâ ÒÊÌ. Ýòî ñâÿçàíî, â òîì ÷èñëå, è ñ òåì, ÷òî
äî ñèõ ïîð íå ðàçðàáîòàíû åäèíûå êðèòåðèè è òðåáîâàíèÿ ê
ïîäãîòîâêå ðàçìîðîæåííîãî òðàíñïëàíòàòà ãåìîïîýòè÷åñêèõ
êëåòîê ïåðåä èíôóçèåé. Òàê, íåäàâíî, âåäóùàÿ îðãàíèçàöèÿ â
Åâðîïå - EBMT (The European Group for Blood and Marrow
Transplantation), ðåãóëèðóþùàÿ äåÿòåëüíîñòü öåíòðîâ ÒÊÌ,
Êëåòî÷íàÿ òðàíñïëàíòîëîãèÿ è òêàíåâàÿ èíæåíåðèÿ ¹ 1 (3), 2006
32
Íîâîñòè êëåòî÷íûõ òåõíîëîãèé
ïðîâåëà îïðîñ ïî òåõíèêå êðèîêîíñåðâàöèè è ïîäãîòîâêå
àóòîòðàíñïëàíòàòà ïåðåä èíôóçèåé. Äàííûå, ïîëó÷åííûå
èç 97 öåíòðîâ, î÷åíü ñèëüíî îòëè÷àëèñü äðóã îò äðóãà êàê
ïî èñïîëüçóåìîé äëÿ êðèîêîíñåðâàöèè êîíöåíòðàöèè
ÄÌÑÎ, òàê è ïî ïîçèöèè «îòìûâêè òðàíñïëàíòàòà» ïåðåä
èíôóçèåé. Îñëîæíåíèÿ, ñâÿçàííûå ñ òîêñè÷íîñòüþ ÄÌÑÎ,
íàáëþäàëèñü ñ ÷àñòîòîé 1 ñëó÷àé èç 70 [4].
Îñíîâíûå âûâîäû è ðåêîìåíäàöèè, îñíîâàííûå íà ñîîáùåíèÿõ î òåõíèêå êðèîêîíñåðâèðîâàíèÿ ñ èñïîëüçîâàíèåì ÄÌÑÎ, ðàçìîðîçêè è èíôóçèè ãåìîïîýòè÷åñêèõ êëåòîê,
ìîæíî ñâåñòè ê ñëåäóþùèì:
1. Áîëüøèíñòâî èññëåäîâàòåëüñêèõ ãðóïï ñêëîíÿåòñÿ ê
ìíåíèþ, ÷òî ñíèæåíèå êîíöåíòðàöèè ÄÌÑÎ äî 5% (âìåñòî
ñòàíäàðòíî èñïîëüçóåìîé 10%), ïðè çàìîðîçêå òðàíñïëàíòàòà íå âëèÿåò íà åãî êà÷åñòâî ïîñëå ðàçìîðîçêè [5-7].
ËÈÒÅÐÀÒÓÐÀ:
1. Higman M.A., Port J.D., Beauchamp N.J. Jr, Chen A.R. Reversible
leukoencephalopathy associated with re-infusion of DMSO preserved stem cells.
Bone Marrow Transplant. 2000; 26: 797–800.
2. Dhodapkar M., Goldberg S.L., Tefferi A., Gertz M.A. Reversible
encephalopathy after cryopreserved peripheral stem cell infusion. Am. J. Hematol.
1994; 45: 187-8.
3. Benekli M., Anderson B., Wentling D. et al. Severe respiratory depression
after dimethylsulphoxide-containing autologous stem cell infusion in a patient with
AL amyloidosis. Bone Marrow Transplant. 2000; 25(12): 1299-301.
4. Windrum P., Morris T.C., Drake M.B. et al. EBMT Chronic Leukaemia
Working Party Complications Subcommittee. Variation in dimethyl sulfoxide use
in stem cell transplantation: a survey of EBMT centres. Bone Marrow Transplant.
2005; 36: 601-3.
5. Bakken A.M., Bruserud O., Abrahamsen J.F. No differences in colony
formation of peripheral blood stem cells frozen with 5% or 10% dimethyl sulfoxide.
J. Hematother. Stem. Cell Res. 2003; 12: 351-8.
6. Abrahamsen J.F., Rusten L., Bakken A.M., Bruserud O. Better preservation
of early hematopoietic progenitor cells when human peripheral blood progenitor
2. Ïðèñóòñòâèå «íàòèâíîé» êîíöåíòðàöèè ÄÌÑÎ â òðàíñïëàíòàòå âî âðåìÿ èíôóçèè êëåòî÷íîé ñóñïåíçèè ìîæåò ïðèâåñòè ê ðÿäó ñåðü¸çíûõ îñëîæíåíèé [1-4].
3. Îòìûâêà òðàíñïëàíòàòà ãåìîïîýòè÷åñêèõ êëåòîê îò
êðèîïðîòåêòîðà íå âëèÿåò íà êîëè÷åñòâî, æèçíåñïîñîáíîñòü
CD34+ êëåòîê è ñêîðîñòü ýíãðàôòèíãà [8, 9].
Òàêèì îáðàçîì, íåîáõîäèìî ñîçäàíèå ñòàíäàðòîâ ïî êðèîêîíñåðâàöèè è ïîäãîòîâêå òðàíñïëàíòàòà ãåìîïîýòè÷åñêèõ
êëåòîê â îíêîãåìàòîëîãè÷åñêîé êëèíèêå. Ïîçèöèÿ áîëüøèíñòâà êëèíè÷åñêèõ ãðóïï – íåîáõîäèìà îòìûâêà êðèîïðîòåêòîðà ÄÌÑÎ ïåðåä èíôóçèåé êëåòîê. Ýòî íå âëèÿåò íà êà÷åñòâî òðàíñïëàíòàòà è ïîçâîëÿåò ïðåäóïðåæäàòü ðàçâèòèå
òîêñè÷åñêèõ îñëîæíåíèé. Òåì áîëåå, ÷òî ñàìà ïðîöåäóðà
«îòìûâêè» çàíèìàåò îêîëî 10-15 ìèíóò è ìîæåò áûòü àâòîìàòèçèðîâàíà [10, 11].
cells are cryopreserved with 5 percent dimethylsulfoxide instead of 10 percent
dimethylsulfoxide. Transfusion 2004; 44: 785-9.
7. Curcoy A.I., Alcorta I., Estella J. et al. Cryopreservation of HPCs with high
cell concentration in 5-percent DMSO for transplantation to children. Transfusion
2002; 42: 962.
8. Syme R., Bewick M., Stewart D. et al. The role of depletion of dimethyl
sulfoxide before autografting: on hematologic recovery, side effects, and toxicity.
Biol. Blood Marrow Transplant. 2004; 10: 135-41.
9. Mazet S., Hecquet O., Espinousse D. et. al. Wasing out DMSO from
thawed peripheral blood progenitor cell bags does not result in loss of CD34+
cells. ISHAGE VII annual symposium (Quebec, Canada, 2001 june 14-17)
abstracts book, abst. # 80.
10. Calmels B., Houze P., Hengesse J.C. et al. Preclinical evaluation of an
automated closed fluid management device: Cytomate, for washing out DMSO
from hematopoietic stem cell grafts after thawing. Bone Marrow Transplant.
2003; 31: 823-8.
11. Rodriguez L., Velasco B., Garcia J., Martin-Henao G.A. Evaluation of an
automated cell processing device to reduce the dimethylsulfoxide from
hematopoietic grafts after thawing. Transfusion 2005; 45: 1391-7.
Ïîäãîòîâèë À.Â. Áåðñåíåâ
Ïî ìàòåðèàëàì Leuk. Lymphoma 2005; 46: 1671-4
Ìåòîä ýíäîñêîïè÷åñêîãî ïîëó÷åíèÿ áèîïòàòà ãîëîâíîãî
ìîçãà è âûäåëåíèÿ èç íåãî íåéðàëüíûõ ñòâîëîâûõ êëåòîê
äëÿ àóòîòðàíñïëàíòàöèè
Ïîëó÷åíèå äîñòàòî÷íîãî êîëè÷åñòâà íåèììóíîãåííûõ
íåéðàëüíûõ êëåòîê ÿâëÿåòñÿ àêòóàëüíîé ïðîáëåìîé êëèíè÷åñêîé íåéðîòðàíñïëàíòàöèè. Äëÿ çàìåùåíèÿ íåôóíêöèîíèðóþùèõ íåðâíûõ êëåòîê èëè ñòèìóëÿöèè íåéðîãåíåçà in
situ â êëèíè÷åñêîé íåéðîòðàíñïëàíòàöèè íóæíû ñïåöèàëèçèðîâàííûå íåðâíûå êëåòêè èëè ïðîãåíèòîðû ñ ïîòåíöèàëîì
ê ðîñòó è äèôôåðåíöèðîâêå â íåéðîíàëüíîì íàïðàâëåíèè.
Íàèáîëåå ðàñïðîñòðàí¸ííûìè èñòî÷íèêàìè òàêîãî êëåòî÷íîãî
ìàòåðèàëà â êëèíèêå ÿâëÿåòñÿ ãîëîâíîé ìîçã àáîðòèðîâàííûõ ýìáðèîíîâ (èëè ïëîäîâ) ÷åëîâåêà [1, 3] è ñîáñòâåííûå
íåéðîíàëüíûå êëåòêè ïàöèåíòà, âûäåëåííûå èç îáîíÿòåëüíîé çîíû ñëèçèñòîé îáîëî÷êè íîñà (olfactory ensheathing
cells) [2].  êà÷åñòâå àëüòåðíàòèâíîãî èñòî÷íèêà êëåòî÷íîãî
ìàòåðèàëà ðàññìàòðèâàþòñÿ àëëîãåííûå íåéðîíàëüíûå ñòâîëîâûå êëåòêè (ÍÑÊ) ãîëîâíîãî ìîçãà òðóïîâ. ÍÑÊ áûëè âûäåëåíû èç ðàçëè÷íûõ îòäåëîâ ãîëîâíîãî ìîçãà (âêëþ÷àÿ êîðó,
ñóáâåíòðèêóëÿðíóþ çîíó, ñåò÷àòêó, ãèïïîêàìï è îáîíÿòåëüíóþ
Êëåòî÷íàÿ òðàíñïëàíòîëîãèÿ è òêàíåâàÿ èíæåíåðèÿ ¹ 1 (3), 2006
çîíó) òðóïîâ â ðàçíîå âðåìÿ ïîñëå ñìåðòè äî 140 ÷àñîâ è
îõàðàêòåðèçîâàíû [4-6]. Îäíàêî, èñïîëüçîâàíèå ýòèõ èñòî÷íèêîâ ÍÑÊ èìååò òå èëè èíûå îãðàíè÷åíèÿ èëè íåäîñòàòêè ìàëîå êîëè÷åñòâî êëåòîê (ôåòàëüíûé ìîçã è àóòîãåííûé
ìàòåðèàë), ïðîáëåìà èíôåêöèîííîé áåçîïàñíîñòè (ôåòàëüíûé è òðóïíûé àëëîãåííûé ìàòåðèàë), ïðîáëåìà îíêîãåííîé áåçîïàñíîñòè (ýìáðèîíàëüíûå ñòâîëîâûå êëåòêè è
èõ äåðèâàòû, ðàííèå âçðîñëûå ñòâîëîâûå êëåòêè) è èììóíîëîãè÷åñêèé êîíôëèêò (àëëîãåííûé è êñåíîãåííûé ìàòåðèàë). Òàêèì îáðàçîì, ïîèñê îïòèìàëüíîãî èñòî÷íèêà
êëåòî÷íîãî ìàòåðèàëà äëÿ çàìåñòèòåëüíîé êëèíè÷åñêîé
íåéðîòðàíñïëàíòàöèè îñòà¸òñÿ àêòóàëüíîé çàäà÷åé. Åñëè
áû ïðîáëåìà äîñòàòî÷íîãî êîëè÷åñòâà êëåòî÷íîãî ìàòåðèàëà áûëà ðåøåíà, òî «èñòî÷íèêîì âûáîðà» ìîãëè áû ñòàòü
àóòîãåííûå ÍÑÊ.
Èññëåäîâàòåëè èç øâåäñêîãî Karolinska Institute ïðåäëàãàþò íîâûé ìåòîä âûäåëåíèÿ è ýêñïàíñèè àóòîãåííûõ ÍÑÊ