COMPARACIÓN DE LOS DETERMINANTES DE DESEMPLEO POR

Murine models have variously imphcated CD4+, CD8-I- and NK cells as effectors in

GvL activity without causing GvHD (Truitt et al 1991b),(Jiang et al 1995),(Jiang et al.

1997), (Giralt et al. 1995), (Hsieh et al 2000), (de, V et al. 1999), (Mutis et al. 1999b).

in C M L and this is supported by good results achieved with CDS depleted D L Is (G iralt et al 1995).

It is also clear that CD 4+ cells can be cytotoxic (G rogg et al 1992) and several groups have raised leukaem ia specific T cell clones from m atched sibling donors (Faber et al.

1992), (Jiang et al 1995) with lineage specificity to CM L cells and norm al m yeloid cells from the recipient but not T or B cells from the sam e individual. How ever, as they did variably react against host-derived haem atopoietic cells, it does suggest that a class II restricted haem atopoietic lineage related m inor histocom patibility antigen may be the target rather than a truly leukaem ia specific antigen. T he CD 4 story may also not be directly applicable to other leukaem ias besides CM L although they m ay still be im portant through the indirect secretion o f cytokines. This may be because C M L cells express M HC class II m olecules which could allow for the direct recognition o f tum our cells by CD 4+ T cells (Johnson et al 1999).

C D 8+ T cells clones reactive with leukaem ia cells have been described (Sosm an et al. 1990), (Falkenburg et al. 1993) and seen in a clinical situation, involving both CD4-I- and C D 8+ G vL effectors (Faber et al 1992). A ttem pts are currently being m ade to expand these leukaem ia-specific T cells.

Further attem pts to characterise G vL T cell effectors have defined them in term s of their cytokine profile secretions, being either T h l/T ^ l if they are y-IFN and IL2 secreting and Th2/Tc2 if IL4 and ILIO are the main cytokines produced (M osm ann et al 1989) It has been reported that the G vL effect is associated with a T h l phenotype in a m urine leukaem ia m odel (Fow ler et al. 1996a), (Fow ler et al. 1996b). On the other hand G vH D is also thought to be m ediated by alloreactive T cells with a type 1

cytokine phenotype and hence the specificity of the GvL effect may not be harnessed

(Krenger et al 1995).

Another population of T cells termed yÔ T cells has been implicated in pure GvL

activity. They are so called because they possess the yÔ heterodimer T cell receptor

rather than a p common to most other T cells and recognise targets in a non MHC

restricted fashion (Fisch et al. 1990). They often respond to intact polypeptides rather

than processed antigen and also to non-peptide based antigens. Although activation

may occur via the the T cell receptor (TCR) (Lanier et al. 1987), recognition is not

based on this and may instead involve lymphocyte function associated antigen-1 (LFA-

1) and intracellular adhesion molecule-1 (ICAM-1) interactions (Ensslin et al 1991).

Their normal range in peripheral blood is 5-10%. An association has been

demonstrated between increased levels of these cells and improved leukaemia free

survival without additional risk of GvHD in a cohort of patients and demonstrated

leukaemia specific killing with in-vitro assays (Lamb, Jr. et al. 1996). They have been

shown to facilitate engraftment in mice (Blazar et al. 1996).

Lymphokine activated killer (LAK) and NK cells have also been implicated (Lowdell

et al. 1997), (Delmon et al. 1986), (Murphy et al 1997), (Zeis et al. 1998). Attempts

have been made to expand these NK cells or to generate LAK cells using IL2, IL l2

(Uharek et al. 1996). Toxicity with in-vivo administration of IL2 remains a problem

and ex-vivo expansion of NK cells has proved difficult although recent reports are

more encouraging (Miller et al 1998). The relative feasibility of haploidentical

transplants has illuminated new aspects of NK cells function. It has been observed that

despite extreme T cell depletion, a low incidence of relapse was observed, especially

significant num bers o f NK and T cells expressing NK m arkers ineluding killer inhibitory receptors (KIRs) appearing early after engraftm ent (Albi et al. 1996). This phenom enon is also seen to a lesser extent, in allogeneic transplants. In a haploidentical transplant, the possibility o f a KIR m ism atch betw een donor and reeipient is high, creating the possibility o f alloreactive NK cells recognising recipient haem atopoietie cells including leukaem ic blasts based upon a lack o f inhibition from the appropriate KIR m olecule (A versa et al. 1998), (Russell et al 1998). These alloreactive N K cells seem to only recognise recipient haem atopoietic cells and not other host tisue, thereby not indueing G vH D (R uggeri et al. 1999). The reasons for this have yet to be fully elucidated but w ould contribute to a G vL effect independent of G vH D . KIR epitope-m ism atching in the GvH direction may thus confer unique potential for G vL effect and engraftm ent. It has also been suggested that allogeneic NK cells contribute to the G vL effect early post BM T w hereas T cells are m ore critical at later tim e points (Johnson et al 1992).

A nother population im plicated in G vL activity are term ed N K -T cells which share characteristics with both N K and T cells although they are derived from CD3-t- T eells (Lu et al 1994), (S chm idt-W olf et al. 1991), (Schm idt-W olf et al. 1993), (Hoyle et al. 1998). They have been shown to effectively eradicate hum an tum our cell lines as well as autologous tum our targets in SC ID m urine m odel system s (Lu et al 1994), (H oyle et al 1998). This cytotoxieity appears to be non-M H C restricted and m ay be regulated by KIRs w hich are present on their cell surface (H oyle et al 1998). In addition, these NK- T cells also produce pro-inflam m atory cytokines such as G M -CSF, y-IFN and T N F -a . U nlike N K cells, there are readily expandable with the use o f cytokines (y-IFN, IL2) and do not require exogenous IL2 for in-vivo activity. They have thus also been called

cytokine induced killer (CIK) cells. Clinical trials are underway. Table 1.2

summarises the properties of these effector cell populations.

Table 1.2: Properties o f GvL effector cell populations

Taken from F orm anS. American Society o f Haematolosv education book 1999)

Prooertv NK CTL NK-T ceils

Phenotype CD3-CD56+CD16+ CD3+CD56-CD8+ CD3+CD56+CD16-

Precursor cell NK T T

Antigen specificity No Yes No

Expandable Limited Yes Yes

IL2 in vivo Yes No No