preventing GVHD

So I'm working on a big post about lupus (and the the the first approval of a drug specifically for lupus in fifty years), but in the meantime, I've assembled some other random thoughts that won't see the light of day unless I kind of word-vomit them out first. So, here goes.

Leukemia and lymphoma, the "liquid tumors," are so named because they arise from malignant transformation of cells whose precursors originate in the bone marrow. Leukemia occurs from overproliferation of precurors to mature hematopoietic cells which lack the function of fully developed WBCs. Lymphoma occurs from acquisition of malignant properties by differentiated white blood cells which have exited the bone marrow. While chemotherapy has shown success in some limited situations (diffuse large B cell lymphoma, for example), these tumors often recur. The last available option is often to replace the patient's entire hematopoietic lineage, via the so-called "bone marrow transplant." Traditionally, this involved two steps; irradition of the host bone marrow, followed by transplantation with new bone marrow from someone whose cells were least likely to be recognized as foreign by any remaining immune cells in the host (aka, maximal HLA matching).

This procedure was first successfully attempted in mice in 1956, and subsequently attempted in humans with refractory disease in 1957 (Thomas et al. N Engl J Med 257:491-6). The same group first successfully achieved temporary remission with BMT in 1959, in a study published in the Journal of Clinical Investigation.

Unfortunately, almost as soon as successful remissions with transplants were describe, so too were significant adverse effects, in which transplanted white blood cells would see the host as foreign and attack it. This destruction, first described in 1957 was largely focused in the skin (causing a sclerosing skin rash), and in the intestine (causing inflammatory diarrhea), known collectively as graft versus host disease. It was demonstrated in 1978 that T cells were critical for the graft versus host response. In order to try and minimize this devastating, and potentially lethal, side effect, early emphasis in BMT development was placed on achieving maximal HLA matching.

Interestingly, in 1979, a paper in the New England Journal of Medicine demonstrated an unexpected finding; patients receiving a mismatched SCT were actually less likely to relapse if they developed GVHD. Based on this, the theory was put forward that donor T cells could have both positive and negative effects; that is, they would seek out and reject tumor cells, but would inflict life-threatening collateral damage on host tissue at the same time. It has since been demonstrated that selective transfer of donor lymphocytes in patients with relapsed disease following non-selective BMT can achieve complete and permanent remission in some cases. Given this, the call for optimizing allogeneic (aka, non-HLA matched) stem cell transplants for graft-mediated tumor rejection while controlling graft versus host disease continues to grow.

One method of minimizing graft versus host disease while permitting anti-tumor immunity seems to be via increasing the presence of regulatory T cells. As shown on the left, in mice, co-transfer of regulatory T cells appears to suppress GVHD while still permitting tumor rejection and significantly improving survival. A role for Tregs is further evidenced by the relatively low rate of GVHD in patients receiving transplants of umbilical cord blood, which appears to be enriched in Tregs. Therefore, the search continues for treatments that might continue to shift this balance in favor of anti-tumor immunity and away from off-target anti-host tissue effects.

A new study in the Journal of Experimental Medicine shows some promise in doing just that. This study focuses on targeting BTLA, an inhibitory, immunoglobulin-family receptor that is expressed on Th1, but not Th2 cells. BTLA interacts with both B7 family members (similar to other co-stimulatory molecules such as CD28) but also with TNF family receptors. Ligation of BTLA induces activation of SHP family phosphatases that limit T cell activation and IL-2 production. It is required for the generation of antigen-specific Tregs in response to antigen without co-stimulation. Interestingly, BTLA expression appears to be downregulated by the presence of bacterial CpG nucleotides. It is further notable that studies have shown persistent BTLA4 expression on anti-tumor, but not anti-viral cytotoxic lymphocytes, suggesting that BTLA may have a critical role in supressing anti-tumor immunity.

In this paper, the authors treated donor bone marrow with an an agonist anti-BTLA antibody prior to transfer and found that it virtually eliminated development of GVHD as measured by clinical scoring, loss of body weight, and development of intestinal mucosal inflammation and ulceration. Further investigation showed that BTLA stimulation decreased effector T cell development while maintaining Treg development, which is in line with evidence of BTLA in inducing tolerance. Of note, treatment with agonist anti-BTLA did not successfully treat GVHD when given 14 days after transfer, suggesting that BTLA's tolerance inducing effects are restricted to initial development and do not diminish effector function of differentiated Teff cells.

Finally, the authors showed in a minimal residual disease model that agonist anti-BTLA treatment did not significantly inhibit graft versus tumor responses, which still required T cell function as evidenced by the poor response of animals receiving T cell depleted transplants. The search for highly efficacious, broadly applicable cell therapy remains elusive, but providing the proper mileu to support development of an optimal balance of anti-tumor immunity and host tolerance will rely on a combination of careful cell selection and subtle skewing of cell differentiation.

I know, that's kind of a weak ending, but I'm just not ready to jump into heart failure, stroke, or asthma tonight. (Yeah and definitely not lupus either)