Wednesday, May 14, 2008

Immunodeficiency 4

It should be noted that stimulation of the T-cell receptor without interaction between CD28 and CD80/CD86 leads to T cell anergy [4]

CTLA-4 is also present on a subpopulation of regulatory T cells that suppress antigen-specific T-cell immune responses. These naturally occurring cells play a central role in the maintenance of peripheral tolerance by suppressing autoreactive T-cell populations. Apart from CTLA-4, regulatory T cells are characterised by the expression of CD4 and CD25 together with Forkhead box P3 (FOXP3), CD62L, glucocorticoid-induced tumour necrosis factor-related protein (GITR), transforming growth factor 1 (TGF-1) and interleukin-10 (IL-10) [18].

In CLL dendritic cells may be derived from peripheral blood monocytes that are phenotypically and functionally normal [19], however the CLL cells themselves are poor APCs [4]. It seems more likely that the immunodeficiency stems from the interaction between B cells and T cells.

The peripheral lymphoid organs host the proliferative core of CLL. The chemokine stromal derived factor 1 (SDF-1) or CXCL12 recruits CLL cells towards the secondary lymphoid organs via their specific CXCR4 receptor [20]. Within the secondary lymphoid organs they form proliferation centres or pseudofollicles. These are indeed parodies of lymphoid follicles in which the CLL cells are able to subvert the normal helper function to their own use while denying it to normal B cells. T cells expressing CD154 interact with CLL B cells through their CD40 receptor activating them and upregulating CD38 and ZAP-70 [20, 21]. The effect on CLL cells of this interaction in the proliferation centre is to increase proliferation rate [22] (though it remains less than that of normal B cells in normal individuals) but also to induce cell cycle arrest and resistance to apoptosis [23].

However, the T cells do not come through the encounter unscathed. It is important to separate the effects of low grade reactivation of herpes viruses on T cells from the effects of their interaction with the tumour cells, but it seems clear that this interaction induces a state of relative T-cell anergy with poor responses in mixed lymphocyte reactions, poor delayed hypersensitivity reactions, Th2 polarisation and reduced expression of CD154. How this comes about is a matter of dispute, but CLL cells express a wide variety of cytokines including interleukins -1 alpha, -2, -4, -5, -6, -8 and -10; interferons -alpha and -gamma; G-CSF and GM-CSF; TNFalpha and TGF-beta. A good case has been made recently for interleukin-6 being responsible for many of the effects [24].

Regulatory T cells are increased in number in CLL and the increase is greatest in patients with the most advanced disease [18]. It is not clear whether this contributes to the immune deficiency, but what is most noticeable is that this population is exquisitely sensitive to treatment with fludarabine as opposed to treatment with alkylating agents. It has been suggested that this might be one of the mechanisms that favours the development of autoimmune haemolytic anaemia after treatment with fludarabine [12].

The suppression of T cells generally by fludarabine is so profound and persistent [25] that it overwhelms the immunodeficiency of the disease itself. Although there were early suggestions that achieving a complete remission might restore the integrity of the immune system and while it is certainly true that some patients have fewer infections following complete responses, the general rule is that patients continue to have a severe immunodeficiency after treatment and in many cases they also have more severe infections. The immune suppression following treatment with alemtuzumab is more severe in that reactivation of herpes viruses is more likely, but tends not to be so long lasting. The suppressive effects of corticosteroids have already been mentioned. Other treatments such as alkylating agents, while not so immunosuppressive, tend not to be so effective and do not ameliorate the disease-related immune defect. Although rituximab is a less effective agent in clearing tumour burden, it does appear to significantly increase serum immunoglobulin production [26].


18. Beyer M, Kochanek M, Darabi K et al. Reduced frequencies and suppressive function of CD4+ CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 2006;106:2018-25.
19. Messmer D, Telusma G, Wasil T et al. Dendritic cells from chronic lymphocytic leukemia patients are normal regardless of Ig V gene mutations status. Mol Med 2004;10:7-12.
20. Deaglio S, Vaisitti T, Aydin S et al. CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential. Blood 2007; 110:4012-21.
21. Patten PEM, Buggins AGS, Richards J et al. CD38 expression in chronic lymphocytic leukemia is regulated by the tumor environment. Blood 2008; 111:5173-81.
22. Messmer BT, Messmer D, Allen SL et al. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest. 2005;115:755-64.
23. Gricks CS, Zahrieh D, Zauls AJ, et al. Differential regulation of gene expression following CD40 activation of leukemic compared to healthy B cells. Blood. 2004;104:4002-9.
24. Buggins AGS, Patten PEM, Richards J, Thomas NSB, Mufti GJ, Devereux S. Tumor-derived IL-6 may contribute to the immunological defect in CLL. Leukemia 2007 online publication, 1 November; doi:10.1038/sj.leu2405015
25. Boldt DH, Van Hoff DD, Kuhn JG, Hersh M. Effect on human peripheral lymphocytes of the in vivo administration of 9--D-arabinofuranosyl-5'-monophosphate (NSC312887) a new purine antimetabolite. Cancer Res 1984; 44:4661-6.
26. Alexandrescu DT, Wiernik-PH. Serum immunoglobulins as a marker for immune restoration after treatment with high dose rituximab for chronic lymphocytic leukemia. Med Oncol 2008 E-published ahead of print.


Paul Garland said...

Dear Dr. Hamblin,

My primary foces at this point is on trying to improve the body's ability to fight off disease.

It doesn't seem like green tea does much to boost the functioning of the immune system. IVIg may help, but this treatment has become very expensive in the last few years.

From my own persepective it seems like eating right, not smoking or drinking, getting daily exercise, and removing oneself from excessively stressful environments seems to be helping a bit.

Are you aware of other things that CLL patients can do?

Best Regards,

Paul Garland
El Paso, Texas

Terry Hamblin said...

Your are pursuing a sensible approach. There seems some evidense that treatment with rituximab alone might restore serum immunoglobulin levels.

Anonymous said...

Decades after the beginning of understanding of the nature of CLL, more than 10 years after the FDA approval of Rituxan, years after the approval of Campath, there are no new drugs on the market for CLL.

I suppose the argument can be made that a complete understanding of the disease must be achieved before any new drugs are investigated.

Meanwhile, tens of thousands of patients die. What about them?